Substituted imidazoles as selective modulators of Bradykinin B2 receptors

ABSTRACT

Disclosed are compounds of the formula:                    
     or the pharmaceutically acceptable non-toxic salts thereof wherein Y, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7  R 7 ′ are variables defined herein, which compounds are modulators of Bradykinin B 2  receptors. These compounds are therefore useful in the diagnosis and treatment of renal diseases, heart failure, hypertension, Meniere&#39;s disease, vaginal inflammation and pain, peripheral circulatory disorders, climacteric disturbance, retinochoroidal circulatory disorders, myocardial ischemia, myocardial infarction, postmyocardial infarction syndrome, angina pectoris, restenosis after percutaneous transluminal coronary angioplasty, hepatitis, liver cirrhosis, pancreatitis, ileus, diabetes, diabetic complications, male infertility, glaucoma, pain, asthma, and rhinitis, and for the increase of permeability of the blood-brain barrier or the blood-brain-tumor barrier.

This application claims priority from U.S. provisional patentapplication no. 60/176,869, filed Jan. 18, 2000.

FIELD OF THE INVENTION

This invention relates to certain imidazoles which, when appropriatelysubstituted, are selective modulators of Bradykinin B₂ receptors (BK-2receptors). This invention also relates to pharmaceutical compositionscomprising such compounds. It further relates to the use of suchcompounds in treating a variety of central and peripheral disorders.Additionally, compounds of this invention are useful as positivecontrols in assays for BK-2 receptor activity and when appropriatelylabeled as probes for the localization of BK-2 receptors in tissuesections.

BACKGROUND

Bradykinin (BK), a nonapeptide, and the closely related decapeptidekallidin (Lys-BK), are produced by proteolytic cleavage of highmolecular weight kininogen by plasma kallikreins. The effects ofbradykinin and kallidin are mediated by specific seven transmembraneG-protein coupled receptors.

The existence of two bradykinin receptor subtypes has been unequivocallyconfirmed within the last six years. The expression and cloning of a ratbradykinin receptor, now known to be a BK-2 receptor, was first reportedfollowed by the cloning and pharmacological characterization of a humanBK-2 receptor. The expression and cloning of a human bradykinin (B₁)receptor has also been described.

Both BK and kallidin activate the B₂ receptor while only kallidin isactive at the B₁ receptor. However, both compounds are rapidly cleavedto produce B₁ receptor agonists, and then further degraded by kinases toproduce inactive peptides. The instability of BK and kallidin suggeststhat these peptides act locally. Both receptors are expressed in anumber of peripheral tissues as well as in the Central Nervous System(CNS).

The B₂ receptor is expressed constitutively in a variety of tissues andaccounts for the majority of the acute pharmacological effects ofbradykinin. The B₁ receptor is inducibly expressed and appears to actpredominantly in pathophysiological conditions. The BK-1 receptor hasbeen especially implicated in persistent hyperalgesia and chronicinflammation.

Bradykinin is an effector of a number of inflammatory responsesincluding bronchoconstriction, plasma extravasation, release ofprostaglandins/leukotrienes, smooth muscle contraction/relaxation andnociception. Bradykinin and the related peptide kallidin have beenimplicated in a number of disease conditions, including but not limitedto pain, rhinitis, anaphylaxis, inflammatory bowel disease, vascularpermeability, algesia, vasodilataion, inflammatory response, hypotensionassociated with sepsis, bronchopulmonary disorders including asthma, andincreased cell proliferation. Antagonists of the BK-2 receptor areuseful in treating these conditions. Additionally bradykinin has beenimplicated in increased glucose uptake, and decreased blood glucoseconcentration. Therefore agonists of the BK-2 receptor may be useful inthe treatment of Type II diabetes. An increased permeability of theblood-brain barrier due to bradykinin has also been reported. Thus,agonists of the BK-2 receptor may also be used to increase the brainlevels of pharmaceutical compounds used to treat central nervous systemdisorders when administered with these compounds. Therefore, compoundsthat modulate the bradykinin B₂ (BK-2) receptor as agonists orantagonists would have considerable therapeutic benefit.

A number of tissues and cultured cell lines have been assessed for thepresence of bradykinin receptors using radiolabeled bradykinin or aradiolabeled bradykinin analogue as a probe (See Hall, Gen. Pharma.,1997, 28: 1-6, for a compilation of such studies.). Although bradykininand its analogues exhibit high affinity for bradykinin receptors thereare some difficulties in using these ligands as receptor localizationprobes. Bradykinin binds to both BK-1 and BK-2 receptors and thereforecannot be used to distinguish receptor subtypes. Also bradykinin andmany of its peptide analogues are susceptible to rapid degradation bykininases, leading to experimental difficulties. Nonpeptidic ligands arenot susceptible to kininase activity. Therefore, small molecules thatbind with high affinity and high selectivity to BK-2 receptors areespecially desirable tools for BK-2 localization studies.

DESCRIPTION OF THE RELATED ART

Various compounds have been prepared as modulators of BK-2 receptors.The following disclose non-peptidic compounds that modulate BradykininB₂ receptors: EP-622361-A1, WO 98/42672, WO 97/41104, WO 97/28153, WO96/13485, EP-596406-A1, EP-835659-A1, EP-808-838-A1, EP-796-848-A1, WO98/03503, WO 97/24349, U.S. Pat. No. 5,438,064, U.S. Pat. No. 5,216,165,U.S. Pat. No. 5,212,182, WO 97/30048, EP 790239-A1, U.S. Pat. No.5,510,380 and U.S. Pat. No. 5,817,756.

The compounds most closely related structurally to those of the presentinvention are a series of2-[(methylamino)methyl]-4,5-dialkyl-1H-imidazoles described asvitronectin receptor antagonists and disclosed in international patentapplications WO 99/06049 and WO 97/24119. These compounds are alsodiscussed by Keenan et. al. (Bioorg. Med. Chem. Lett. (1998), 9(22):3165-3170) and by Reader (Synlett (1998), (10): 1077-1078). Thecompounds described in these publications are not disclosed asbradykinin antagonists and they are not contained in the presentinvention.

SUMMARY OF THE INVENTION

This invention provides novel compounds of Formula I (shown below) andpharmaceutical compositions comprising compounds of Formula I. Suchcompounds exhibit high selectivity for bradykinin B₂ receptors.Compounds of Formula I also bind with high affinity to these receptors.

The invention further provides methods of treating patients sufferingfrom certain inflammatory disorders and other conditions mediated bybradykinin. The invention also provides methods of treating patients(humans and non-humans) suffering from conditions in which agonism ofthe BK-2 receptor may prove beneficial. Treatment of humans,domesticated companion animals (pets) or livestock animals sufferingsuch conditions with an effective amount of a compound of the inventionis contemplated by the invention.

In a separate aspect, the invention provides methods of using compoundsof this invention as positive controls in assays for BK-2 receptoractivity and using appropriately labeled compounds of the invention asprobes for the localization of BK-2 receptors in tissue sections.

A broad aspect of the invention is directed to compounds of Formula I:

or the pharmaceutically acceptable non-toxic salts thereof wherein:

R₁ is arylalkyl, preferably benzyl (with the proviso that R₁ may not be3-Fluorobenzyl), heteroarylalkyl preferably quinolinylmethyl or picolyl,or allyl, each of which which is optionally substituted directly orthrough a O(CH₂)_(n) linker (where n=1, 2, 3 or 4) with up to threesubstituents independently selected from:

(i) halogen (with the proviso that R₁ may not be 3-Fluorobenzyl), nitro,trifluoromethyl, trifluoromethoxy, cyano, hydroxyl, C₁-C₆ alkyl, amino,C₁-C₆ alkoxy, aminomethyl, mono or di(C₁-C₆)alkylamino, mono ordialkylaminomethyl, (wherein each alkyl is independently lower (C₁-C₆)alkyl),

(ii) C₁-C₆alkoxyNR₈R₉, NR₈R₉, NR₈COR₉, CONR₈R₉,

wherein R₈ and R₉ are the same or different and represent hydrogen,straight or branched chain lower alkyl, or R₈ and R₉ form a 5, 6, or 7membered heterocyclic ring, which is optionally substituted withhalogen, nitro, trifluoromethyl, cyano, hydroxyl, C₁-C₆ alkyl, amino,mono or di(C₁-C₆)alkylamino, or C₁-C₆ alkoxy,

(iii) O(CH₂)_(n)CO₂R_(A) wherein n=1, 2, 3, 4, COR_(A), and CO₂R_(A),

wherein R_(A) represents hydrogen, or straight or branched chain loweralkyl,

(iv) SO₂R_(A), NHSO₂R_(A), SO₂NHR_(A), SO₂NHCOR_(A), CONHSO₂R_(A),

wherein R_(A) represents hydrogen, or straight or branched chain loweralkyl,

(v) tetrazole, triazole, imidazole, thiazole, oxazole, thiophene, andpyridyl;

R₂ and R₃ are the same or different and represent

(i) halogen, trifluoromethyl, trifluoromethoxy, lower alkoxy having 1-6carbon atoms, lower alkyl, amino methyl, mono or dialkylaminomethyl,wherein each alkyl is independently lower (C₁-C₆) alkyl,

(ii) C₁-C₆alkoxyNR₈′R₉′, NR₈′R₉′, CONR₈′R₉′, NR₈′COR₉′, wherein R₈′ andR₉′ are the same or different and represent hydrogen or straight orbranched chain lower alkyl, or R₈′ and R₉′ is a 5, 6, or 7 memberedheterocyclic ring, optionally substituted with halogen, nitro,trifluoromethyl, cyano, hydroxyl, C₁-C₆ alkyl, amino, mono ordi(C₁-C₆)alkylamino, or C₁-C₆ alkoxy,

(iii) O(CH₂)_(n)CO₂R_(A)′ where n=1, 2, 3, 4, COR_(A)′, or CO₂R_(A)′,

wherein R_(A)′ represents hydrogen or straight or branched chain loweralkyl; or

R₂ and R₃ may be taken together to form a carbocyclic or heterocyclicsaturated ring;

R₄ represents straight or branched chain lower alkyl;

R₅ represents halogen or trifluoromethyl;

R₆, R₇ and R₇′ are the same or different and represent

(i) hydrogen, trifluoromethyl, trifluoromethoxy, nitrile, C₁-C₁₀ alkyl,C₁-C₁₀ alkoxy (with the proviso that R₆, R₇, or R₇′ may not be C₁-C₁₀alkoxy when located ortho to Y), C₁-C₆alkylthio, halogen, aminomethyl,di(C₁-C₆)alkylamino, mono or diC₁-C₆alkylaminomethyl, or

(ii) C₁-C₆ alkoxyaminoalkyl where the amino is mono or disubstitutedwith straight or branched chain lower alkyl;

(iii) or any two adjacent R₆, R₇ or R₇′ may be joined to form a 5 to 7membered ring containing 1 or 2 oxygen atoms where the remaining ringmembers are carbon; or

R₅ and R₆ are joined to form a 5, 6, or 7 membered carbocyclic orheterocyclic aromatic ring which is optionally substituted with up tofour substituents selected from:

(i) halogen, nitro, trifluoromethyl, cyano, hydroxyl, C₁-C₆ alkyl,amino, C₁-C₆ alkoxy, aminomethyl, alkylaminomethyl, mono ordi(C₁-C₆)alkylamino, mono or dialkylaminomethyl, wherein each alkyl isindependently lower (C₁-C₆) alkyl,

(ii) C₁-C₆alkoxyNR₈″R₉″, NR₈″R₉″, CONR₈″R₉″, NR₈″COR₉″, where R₈″ andR₉″ are the same or different and represent hydrogen or straight orbranched chain lower alkyl, or R₈″ and R₉″ can be a 5, 6, or 7 memberedheterocyclic ring, which is optionally substituted with halogen, nitro,trifluoromethyl, cyano, hydroxyl, lower alkyl, amino, mono ordi(C₁-C₆)alkylamino, or C₁-C₆ alkoxy,

(iii) O(CH₂)_(n)CO₂R_(A)″ where n=1, 2, 3, 4, COR_(A)″, or CO₂R_(A)″,wherein R_(A)″ represents hydrogen or straight or branched chain loweralkyl; and R₇ and R_(7′) are as defined above; and

Y represents a bond or CH₂, when Y=CH₂ it may be mono or disubstitutedwith a straight or branched chain lower alkyl, or straight or branchedchain lower alkoxy having 1-6 carbon atoms.

DETAILED DESCRIPTION OF THE INVENTION

The novel compounds of Formula I may be comprised of compounds ofgeneral Formula Ia:

or the pharmaceutically acceptable non-toxic salts thereof wherein: R₁,R₂, R₃, R₄, and Y are as defined above;

R₅ represents halogen, hydrogen, or trifluoromethyl; and

R₆, R₇ and R₇′ are the same or different and represent hydrogen,trifluoromethyl, trifluoromethoxy, cyano, nitro, lower alkyl having 1-10carbon atoms, C₁-C₁₀ alkoxy (with the proviso that R₆, R₇, or R₇′ maynot be C₁-C₁₀ alkoxy when located ortho to Y in Formula Ia), halogen,aminomethyl, mono or dialkylaminomethyl where each alkyl isindependently lower (C₁-C₆) alkyl, and C₁-C₆ alkoxyaminoalkyl where theamino is mono or disubstituted with straight or branched chain loweralkyl having 1-6 carbon atoms.

Preferred compounds of the invention are comprised of compounds ofFormula I or Formula Ia, and the pharmaceutically acceptable saltsthereof, wherein R₁, R₄, R₅, R₆, R₇, R₇′ and Y are as defined forFormula I or Formula Ia with the restriction that R₂ and R₃ do not forma carbocyclic or heterocyclic ring.

Other novel compounds of Formula I may be comprised of compounds ofgeneral Formula Ib:

or the pharmaceutically acceptable non-toxic salts thereof wherein: R₁,R₂, R₃, R₄, and Y are as defined above;

R₅ is part of an aromatic ring formed with R₆;

R₆ is part of an 5, 6, or 7 membered aromatic ring which is optionallysubstituted with halogen, nitro, trifluoromethyl, cyano, hydroxyl, C₁-C₆alkyl, amino, or mono or di(C₁-C₆)alkylamino, C₁-C₆ alkoxy, aminomethyl,alkylaminomethyl or mono or dialkylaminomethyl where each alkyl isindependently lower (C₁-C₆) alkyl, C₁-C₆ alkoxyaminoalkyl (for exampleOCH₂CH₂NR₈″R₉″), NR₈″R₉″, CONR₈″R₉″, NR₈″COR₉″, where R₈″ and R₉″ arethe same or different and represent hydrogen or straight or branchedchain lower alkyl having 1-6 carbon atoms, additionally R₈″ and R₉″ canbe a 5, 6, or 7 membered heterocyclic ring, which may be optionallysubstituted with halogen, nitro, trifluoromethyl, cyano, hydroxyl, C₁-C₆alkyl, amino, mono or di(C₁-C₆)alkylamino, or C₁-C₆ alkoxy;

O(CH₂)_(n)CO₂R₈″ where n=1, 2, 3, 4, COR₈″, or CO₂R₈″, where R₈″represents hydrogen or straight or branched chain lower alkyl having 1-6carbon atoms; and

R₇ and R₇′ represent hydrogen, trifluoromethyl, trifluoromethoxy, cyanoor nitro, lower alkyl having 1-10 carbon atoms, C₁-C₁₀ alkoxy (with theproviso that R₆, R₇, or R₇′ may not be C₁-C₁₀ alkoxy when located orthoto Y in Formula Ib), halogen, aminomethyl, mono or dialkylaminomethylwhere each alkyl is independently lower (C₁-C₆) alkyl, or C₁-C₆alkoxyaminoalkyl where the amino is mono or disubstituted with straightor branched chain lower alkyl having 1-6 carbon atoms.

Preferred compounds of Formula Ib include those compound in which R₁,R₄, R₅, R₆, R₇, and R_(7′) are as defined for Formula Ib and R₂ and R₃are defined as for Formula Ib with the restriction that R₂ and R₃ do notform a ring.

One preferred embodiment of the present invention encompasses compoundsof Formula II and the pharmaceutically acceptable salts thereof;

wherein R₁ and R₄ are as defined above.

In a more preferred embodiment the invention encompasses compounds ofFormula II and the pharmaceutically acceptable salts thereof wherein R₄is isoamyl or n-pentyl, and R₁ is as defined above.

In another preferred embodiment, the present invention encompassescompounds of Formula III, and the pharmaceutically acceptable saltsthereof;

wherein R₁ and R₄ are as defined above.

In a more preferred embodiment the invention encompasses compounds ofFormula III and the pharmaceutically acceptable salts thereof wherein R₄is iso amyl or n-pentyl, and R₁ is as defined above.

In certain situations, the compounds of Formula I may contain one ormore asymmetric carbon atoms, so that the compounds can exist indifferent stereoisomeric forms. These compounds can be, for example,racemates or optically active forms. In these situations, the singleenantiomers, i.e., optically active forms, can be obtained by asymmetricsynthesis or by resolution of the racemates. Resolution of the racematescan be accomplished, for example, by conventional methods such ascrystallization in the presence of a resolving agent, or chromatography,using, for example a chiral HPLC column.

Representative compounds of the present invention, which are encompassedby Formula I, include, but are not limited to the compounds described inthe Examples and their pharmaceutically acceptable acid addition salts.In addition, if the compound of the invention is obtained as an acidaddition salt, the free base can be obtained by basifying a solution ofthe acid salt. Conversely, if the product is a free base, an additionsalt, particularly a pharmaceutically acceptable addition salt, may beproduced by dissolving the free base in a suitable organic solvent andtreating the solution with an acid, in accordance with conventionalprocedures for preparing acid addition salts from base compounds.

Non-toxic pharmaceutical salts include salts of acids such ashydrochloric, phosphoric, hydrobromic, sulfuric, sulfinic, formic,toluenesulfonic, methanesulfonic, nitric, benzoic, citric, tartaric,maleic, hydroiodic, alkanoic such as acetic, HOOC—(CH₂)n—COOH where n is0-4, and the like. Those skilled in the art will recognize a widevariety of non-toxic pharmaceutically acceptable addition salts.

The present invention also encompasses the acylated prodrugs of thecompounds of Formula I. Those skilled in the art will recognize varioussynthetic methodologies which may be employed to prepare non-toxicpharmaceutically acceptable addition salts and acylated prodrugs of thecompounds encompassed by Formula I.

When any variable occurs more than one time in any constituent orformula for a compound, its definition at each occurrence is independentof its definition at every other occurrence. Thus, for example, if agroup is shown to be substituted with 0-2 R*, then said group mayoptionally be substituted with up to two R* groups and R* at eachoccurrence is selected independently from the definition of R*. Also,combinations of substituents and/or variables are permissible only ifsuch combinations result in stable compounds.

The term “aryl” in the present invention means a monocyclic or bicyclicaromatic group having preferably 6 to 10 carbon atoms, such as, forexample, phenyl or naphthyl.

By “arylalkyl” or “heteroarylalkyl” in the present invention is meant abranched or straight-chain alkyl group having from 1 to about 6 carbonatoms and substituted on one of the carbon atoms by an optionallysubstituted aryl or heteroaryl ring, such as, for example, benzyl,phenethyl, methylpyridyl, ethylpyridyl, and the like.

By “alkyl” in the present invention is meant C₁-C₁₀ alkyl, i.e.,straight or branched chain alkyl groups having 1-10 carbon atoms,preferably 1-6 carbon atoms (C₁-C₆ alkyl), such as, for example, methyl,ethyl, propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, pentyl,2-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl, 3-hexyl, and3-methylpentyl. Preferred C₁-C₁₀ alkyl groups are methyl, ethyl, propyl,butyl, cyclopropyl or cyclopropylmethyl.

By “lower alkyl” in the present invention is meant C₁-C₆ alkyl, i.e.,straight or branched chain alkyl groups having 1-6 carbon atoms.

By “alkoxy” or “lower alkoxy” in the present invention is meant C₁-C₆alkoxy, i.e., straight or branched chain alkoxy groups having 1-6 carbonatoms, such as, for example, methoxy, ethoxy, propoxy, isopropoxy,n-butoxy, sec-butoxy, tert-butoxy, pentoxy, 2-pentyl, isopentoxy,neopentoxy, hexoxy, 2-hexoxy, 3-hexoxy, and 3-methylpentoxy.

By “halogen” in the present invention is meant fluorine, bromine,chlorine, and iodine.

By “(hetero) cyclic ring” is meant a ring that is either aliphatic oraromatic and optionally contains at least one hetero atom. Hetero atomsinclude nitrogen, sulfur, and oxygen. Examples of such (hetero) cyclicrings are cyclohexyl, cyclopentyl, piperidinyl, piperazinyl,pyrrolidinyl, morpholinyl, etc.

By “heteroaryl” (aromatic heterocycle) in the present invention is meantone or more aromatic ring systems of 5-, 6-, or 7-membered ringscontaining at least one and up to four hetero atoms selected fromnitrogen, oxygen, or sulfur. Such heteroaryl groups include, forexample, thienyl, furanyl, thiazolyl, imidazolyl, (is)oxazolyl, pyridyl,pyrimidinyl, imidazolyl, (iso)quinolinyl, naphthyridinyl,benzimidazolyl, and benzoxazolyl.

Specific examples of heteroaryl groups are the following:

wherein:

L is nitrogen or —CR¹¹;

T is —NR¹⁹, oxygen, or sulfur;

R¹¹ and R^(11′) are the same or different and are selected from:hydrogen, halogen, hydroxy, C₁-C₆ alkyl, (C₁-C₆)alkoxy, amino, or mono-or di(C₁-C₆)alkylamino;

R¹², R^(12′), and R¹³ are the same or different and are selected fromhydrogen, halogen, (C₁-C₆)alkyl, (C₁-C₆)alkoxy, amino, mono- ordi(C₁-C₆)alkylamino, hydroxy, or trifluoromethyl; and

R¹⁹ is hydrogen, or lower alkyl having 1-6 carbon atoms.

The structure of Formula I as shown in the specification and as used inthe claims includes all possible tautomers and rotamers.

The invention also provides pharmaceutical composition comprisingcompounds of the invention.

The invention also provides packaged pharmaceutical compositionscomprising pharmaceutical compositions of the invention in a containerand instructions for using the composition to treat a patient in needthereof. In one embodiment, the instructions are for using thecomposition for treating a patient suffering from a physiologicaldisorder associated with an excess of or insufficient amount ofbradykinin. The patient may be suffering, for example, from renaldisease, heart failure, hypertension, Meniere's disease, vaginalinflammation and pain, peripheral circulatory disorders, climactericdisturbance, retinochoroidal circulatory disorders, myocardial ischemia,myocardial infarction, postmyocardial infarction syndrome, anginapectoris, restenosis after percutaneous transluminal coronaryangioplasty, hepatitis, liver cirrhosis, pancreatitis, ileus, diabetes,diabetic complications, male infertility or glaucoma, asthma, rhinitis,brain cancer, or a brain tumor.

The invention further provides methods of treating patients in sufferingfrom an inflammatory disorder with an amount of a compound of theinvention sufficient to alter the symptoms of the inflammatory disorder.Inflammatory disorders that may be treated with a selective antagonistof the BK-2 receptor include restenosis after percutaneous transluminalcoronary angioplasty, rhinitis, inflammation associated with braintrauma, stroke, sepsis, anaphylaxis, Meniere's disease, pancreatitis,ileus, inflammatory bowel disease, and bronchopulmonary disordersincluding asthma. The invention also provides methods of treatingpatients suffering from pain with a pain-reducing amount of a compoundof the invention. Painful conditions that may be treated with anantagonist of the BK-2 receptor, include, but are not limited toinflammatory pain, postoperative pain, and vaginal inflammation andpain. The invention further provides a method of treating patientssuffering from hypertension with an amount of compound of the inventionsufficient to reduce blood pressure. Selective antagonists of the BK-2receptor are useful as anti-hypertensives.

In a further aspect the invention provide a method of treating a patientsuffering from Type II (adult-onset) diabetes with an amount of acompound of the invention sufficient to alter the symptoms. Selectiveagonists of the BK-2 receptor are useful for treating type II diabetes.The invention also provides methods of treating patients suffering fromcirculatory or cardiovascular disorders with an amount of a compound ofthe invention, that is a selective agonist of the BK-2 receptor,sufficient to reduce the symptoms of the circulatory of cardiovasculardisorder. Such circulatory or cardiovascular disorders include, but arenot limited to heart failure, peripheral circulatory disorders,myocardial infarction, postmyocardial infarction syndrome, anginapectoris, retinochoroidal circulatory disorders, and myocardialischemia. Selective agonists of the BK-2 stimulate NO release and assuch are useful for treating climacteric disturbance and maleinfertility. The invention provides methods of treating patientssuffering from such disorders with an amount of a compound of theinvention sufficient to reduce the symptoms of disorder.

Bradykinin has been shown to increase the permeability of blood-brainbarrier and blood-brain tumor barrier. The invention provides a methodof increasing the brain concentration of a CNS active compounds whichcomprises administering a patient in need of such treatment a compoundof the invention, that is a selective agonist of the BK-2 receptor,along with a CNS active compound, and thereby increasing the brainconcentration of the CNS active compound. In a particularly preferredembodiment the invention provides a method of increasing the brainconcentration of anti-cancer and anti-tumor agents which comprisesadministering a patient suffering from brain cancer or a brain tumor acompound of the invention, that is a selective agonist of the BK-2receptor, along with a anti-cancer and anti-tumor agent, and therebyincreasing the brain concentration of the anti-cancer or anti-tumoragent.

Patients include human and non-human animals, such as domestic pets andfarm animals (for example, dogs, cats, swine, sheep, horses, cattle,etc.).

The present invention also pertains to methods of inhibiting the bindingof bradykinin to the bradykinin receptors, especially BK-2 receptorswhich methods involve contacting a compound of the invention with cellsexpressing bradykinon receptors, (preferably BK-2 receptors) wherein thecompound is present at a concentration sufficient to inhibit the bindingof bradykinin to bradykinin receptors in vitro. This method includesinhibiting the binding of bradykinin to bradykinin receptors in vivo,e.g., in a patient given an amount of a compound of formula I or any ofthe subformulae thereof, that would be sufficient to inhibit the bindingof bradykinon to BK-2 receptors in vitro. The amount of a compound thatwould be sufficient to inhibit the binding bradykinin to the BK-2receptor may be readily determined via a BK-2 receptor binding assay,such as the assay described in Example 8. The BK-2 receptors used todetermine in vitro binding may be obtained from a variety of sources,for example from preparations of rat brain or from cells expressingcloned human BK-2 receptors.

The present invention also pertains to methods for altering thesignal-transducing activity of bradykinin receptors, said methodcomprising exposing cells expressing such receptors to an effectiveamount of a compound of the invention. This method includes altering thesignal-transducing activity of BK-2 receptors in vivo, e.g., in apatient given an amount of a compound of formula I, or the subformulaethereof, that would be sufficient to alter the signal-transducingactivity of BK-2 receptors in vitro. The amount of a compound that wouldbe sufficient to alter the signal-transducing activity of bradykininreceptors may be determined via a bradykinin receptor signaltransduction assay, such as the assay described in Example 9. Thebradykinin receptor ligands (i.e. the compounds of the invention)provided by this invention and labeled derivatives thereof are alsouseful as standards and reagents in determining the ability of apotential pharmaceutical to bind to the BK-2 receptor.

Isotopically-labeled compounds of this invention, which are identical tothose recited in formula I, or the subformulae thereof, but for the factthat one or more atoms are replaced by an atom having an atomic mass ormass number different from the atomic mass or mass number usually foundin nature, are also useful for mapping the location of bradykininreceptors (e.g., in tissue sections via autoradiography) and asradiotracers for positron emission tomography (PET) imaging, singlephoton emission computerized tomography (SPECT), and the like, tocharacterize such receptors in living subjects. Examples of isotopesthat can be incorporated into compounds of the invention includeisotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorineand chlorine, such as ²H, ³H, ¹¹C, ¹³C, ¹⁴C, ¹⁵N, ¹⁸O, ¹⁷O, ³¹P, ³²P,³⁵S, ¹⁸F, and ³⁶Cl, respectively. Compounds of the present invention,prodrugs thereof, and pharmaceutically acceptable salts of saidcompounds or of said prodrugs which contain the aforementioned isotopesand/or other isotopes of other atoms are within the scope of thisinvention. In addition, substitution with heavy isotopes such asdeuterium, i.e., ²H, can afford certain therapeutic advantages resultingfrom greater metabolic stability, for example increased in vivohalf-life or reduced dosage requirements and, hence, may be preferred insome circumstances. Isotopically labeled compounds of formula Ia, or thesubformulae thereof, of this invention and prodrugs thereof cangenerally be prepared by carrying out the procedures disclosed in theSchemes and/or in the examples below, by substituting a readilyavailable isotopically labeled reagent for a non-isotopically labeledreagent.

Pharmaceutical Preparations

The compounds of general Formula I may be administered orally,topically, parenterally, by inhalation or spray or rectally in dosageunit formulations containing conventional non-toxic pharmaceuticallyacceptable carriers, adjuvants and vehicles. The term parenteral as usedherein includes percutaneous, subcutaneous, intravascular (e.g.,intravenous), intramuscular, or intrathecal injection or infusiontechniques and the like. In addition, there is provided a pharmaceuticalformulation comprising a compound of general Formula I and apharmaceutically acceptable carrier. One or more compounds of generalFormula I may be present in association with one or more non-toxicpharmaceutically acceptable carriers and/or diluents and/or adjuvantsand if desired other active ingredients. The pharmaceutical compositionscontaining compounds of general Formula I may be in a form suitable fororal use, for example, as tablets, troches, lozenges, aqueous or oilysuspensions, dispersible powders or granules, emulsion, hard or softcapsules, or syrups or elixirs.

Compositions intended for oral use may be prepared according to anymethod known to the art for the manufacture of pharmaceuticalcompositions and such compositions may contain one or more agentsselected from the group consisting of sweetening agents, flavoringagents, coloring agents and preservative agents in order to providepharmaceutically elegant and palatable preparations. Tablets contain theactive ingredient in admixture with non-toxic pharmaceuticallyacceptable excipients that are suitable for the manufacture of tablets.These excipients may be for example, inert diluents, such as calciumcarbonate, sodium carbonate, lactose, calcium phosphate or sodiumphosphate; granulating and disintegrating agents, for example, cornstarch, or alginic acid; binding agents, for example starch, gelatin oracacia, and lubricating agents, for example magnesium stearate, stearicacid or talc. The tablets may be uncoated or they may be coated by knowntechniques. In some cases such coatings may be prepared by knowntechniques so as to delay disintegration and absorption in thegastrointestinal tract and thereby provide a sustained action over alonger period. For example, a time delay material such as glycerylmonosterate or glyceryl distearate may be employed.

Formulations for oral use may also be presented as hard gelatin capsuleswherein the active ingredient is mixed with an inert solid diluent, forexample, calcium carbonate, calcium phosphate or kaolin, or as softgelatin capsules wherein the active ingredient is mixed with water or anoil medium, for example peanut oil, liquid paraffin or olive oil.

Aqueous suspensions contain the active materials in admixture withexcipients suitable for the manufacture of aqueous suspensions. Suchexcipients are suspending agents, for example sodiumcarboxymethylcellulose, methylcellulose, hydropropylmethylcellulose,sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia;dispersing or wetting agents may be a naturally-occurring phosphatide,for example, lecithin, or condensation products of an alkylene oxidewith fatty acids, for example polyoxyethylene stearate, or condensationproducts of ethylene oxide with long chain aliphatic alcohols, forexample heptadecaethyleneoxycetanol, or condensation products ofethylene oxide with partial esters derived from fatty acids and ahexitol such as polyoxyethylene sorbitol monooleate, or condensationproducts of ethylene oxide with partial esters derived from fatty acidsand hexitol anhydrides, for example polyethylene sorbitan monooleate.The aqueous suspensions may also contain one or more preservatives, forexample ethyl, or n-propyl p-hydroxybenzoate, one or more coloringagents, one or more flavoring agents, and one or more sweetening agents,such as sucrose or saccharin.

Oily suspensions may be formulated by suspending the active ingredientsin a vegetable oil, for example arachis oil, olive oil, sesame oil orcoconut oil, or in a mineral oil such as liquid paraffin. The oilysuspensions may contain a thickening agent, for example beeswax, hardparaffin or cetyl alcohol. Sweetening agents and flavoring agents may beadded to provide palatable oral preparations. These compositions may bepreserved by the addition of an anti-oxidant such as ascorbic acid.

Dispersible powders and granules suitable for preparation of an aqueoussuspension by the addition of water provide the active ingredient inadmixture with a dispersing or wetting agent, suspending agent and oneor more preservatives. Suitable dispersing or wetting agents andsuspending agents are exemplified by those already mentioned above.Additional excipients, for example sweetening, flavoring and coloringagents, may also be present.

Pharmaceutical compositions of the invention may also be in the form ofoil-in-water emulsions. The oily phase may be a vegetable oil or amineral oil or mixtures of these. Suitable emulsifying agents may benaturally-occurring gums, for example gum acacia or gum tragacanth,naturally-occurring phosphatides, for example soy bean, lecithin, andesters or partial esters derived from fatty acids and hexitol,anhydrides, for example sorbitan monoleate, and condensation products ofthe said partial esters with ethylene oxide, for example polyoxyethylenesorbitan monoleate. The emulsions may also contain sweetening andflavoring agents.

Syrups and elixirs may be formulated with sweetening agents, for exampleglycerol, propylene glycol, sorbitol, glucose or sucrose. Suchformulations may also contain a demulcent, a preservative and flavoringand coloring agents. The pharmaceutical compositions may be in the formof a sterile injectable aqueous or oleaginous suspension. Thissuspension may be formulated according to the known art using thosesuitable dispersing or wetting agents and suspending agents that havebeen mentioned above. The sterile injectable preparation may also besterile injectable solution or suspension in a non-toxic parentallyacceptable diluent or solvent, for example as a solution in1,3-butanediol. Among the acceptable vehicles and solvents that may beemployed are water, Ringer's solution and isotonic sodium chloridesolution. In addition, sterile, fixed oils are conventionally employedas a solvent or suspending medium. For this purpose any bland fixed oilmay be employed including synthetic mono-or diglycerides. In addition,fatty acids such as oleic acid find use in the preparation ofinjectables.

The compounds of general Formula I may also be administered in the formof suppositories, e.g., for rectal administration of the drug. Thesecompositions can be prepared by mixing the drug with a suitablenon-irritating excipient that is solid at ordinary temperatures butliquid at the rectal temperature and will therefore melt in the rectumto release the drug. Such materials are cocoa butter and polyethyleneglycols.

Compounds of general Formula I may be administered parenterally in asterile medium. The drug, depending on the vehicle and concentrationused, can either be suspended or dissolved in the vehicle.Advantageously, adjuvants such as local anesthetics, preservatives andbuffering agents can be dissolved in the vehicle.

Dosage levels of the order of from about 0.1 mg to about 140 mg perkilogram of body weight per day are useful in the treatment of theabove-indicated conditions (about 0.5 mg to about 7 g per patient perday). The amount of active ingredient that may be combined with thecarrier materials to produce a single dosage form will vary dependingupon the host treated and the particular mode of administration. Dosageunit forms will generally contain between from about 1 mg to about 500mg of an active ingredient.

It will be understood, however, that the specific dose level for anyparticular patient will depend upon a variety of factors including theactivity of the specific compound employed, the age, body weight,general health, sex, diet, time of administration, route ofadministration, and rate of excretion, drug combination and the severityof the particular disease undergoing therapy.

Preferred compounds of the invention will have certain pharmacologicalproperties. Such properties include, but are not limited to oralbioavailability, low toxicity, low serum protein binding and desirablein vitro and in vivo half-lives. Penetration of the blood brain barrierfor compounds used to treat CNS disorders is necessary, while low brainlevels of compounds used to treat peripheral disorders are oftenpreferred.

Assays may be used to predict these desirable pharmacologicalproperties. Assays used to predict bioavailability include transportacross human intestinal cell monolayers, including Caco-2 cellmonolayers. Toxicity to cultured hepatocytes may be used to predictcompound toxicity. Penetration of the blood brain barrier of a compoundin humans may be predicted from the brain levels of the compound inlaboratory animals given the compound intravenously.

Serum protein binding may be predicted from albumin binding assays. Suchassays are described in a review by Oravcová, et al. (Journal ofChromatography B 1996, 677, 1-27).

Compound half-life is inversely proportional to the frequency of dosageof a compound. In vitro half-lives of compounds may be predicted fromassays of microsomal half-life as described by Kuhnz and Gieschen (DrugMetabolism and Disposition 1998, 26, 1120-1127).

As discussed above, preferred compounds of the invention exhibit goodactivity in in vitro Bradykinin receptor binding assays, especially BK-2receptor binding assays, and specifically the assay as specified inExample 8, which follows. References herein to “in vitro BK-2 receptorbinding assay” are intended to refer to that protocol as defined inExample 8 which follows.

For administration to non-human animals, the composition may also beadded to the animal feed or drinking water. It will be convenient toformulate these animal feed and drinking water compositions so that theanimal takes in an appropriate quantity of the composition along withits diet. It will also be convenient to present the composition as apremix for addition to the feed or drinking water.

EXAMPLES

Compounds of the invention can be prepared using the reactions depictedin Schemes 1 to 3.

In Scheme 1, L represents an appropriate leaving group such as chloride,bromide, iodide or mesylate. The groups R₁, R₂, R₃, R₄, R₅, R₆, R₇, R₇′and Y are as defined as Formula I.

Alternatively, appropriately protected forms of R₁, R₂, R₃, R₄, R₅, R₆,R₇ and R₇′ may be employed. In such cases, an additional deprotectionstep is employed to obtain the final product. Suitable protecting groupsand conditions are readily available (e.g. “Protective Groups in OrganicSynthesis” by T. W. Greene). Suitable conditions for carrying out thetransformations in Scheme 1 are exemplified but not limited to thosegiven in Example 1. Those skilled in the art will realize that alternatesynthetic methods may be employed to accomplish the reactions in Scheme1.

In Scheme 2, L represents an appropriate leaving group such as chloride,bromide, iodide or mesylate. The groups R₁, R₂, R₃, R₄, R₅, R₆, R₇, R₇′and Y are as defined as Formula I.

Alternatively, appropriately protected forms of R₁, R₂, R₃, R₄, R₅, R₆,R₇ and R₇′ may be employed. In such cases, an additional deprotectionstep is employed to obtain the final product. Suitable protecting groupsand conditions are readily available (e.g. “Protective Groups in OrganicSynthesis” by T. W. Greene). Suitable conditions for carrying out thetransformations in Scheme 2 are exemplified but not limited to thosegiven in Example 2. Those skilled in the art will realize that alternatesynthetic methods may be employed to accomplish the reactions in Scheme2.

In Scheme 3, Z represents hydrogen, bromine, chorine or othersubstituents consistent with the definition of R₁ in Formula I. Thegroups R₁, R₂, R₃, R₄, R₅, R₆, R₇, R₇′ and Y are as defined as FormulaI. Alternatively, appropriately protected forms of R₁, R₂, R₃, R₄, R₅,R₆, R₇ and R₇′ may be employed. In such cases, an additionaldeprotection step is employed to obtain the final product. Suitableprotecting groups and conditions are readily available (e.g. “ProtectiveGroups in Organic Synthesis” by T. W. Greene). The compound R^(I)L is anelectrophile chosen so as to produce substitution in compound 11 that isconsistent with Formula I. In some cases R^(I) in 11 may be furthermodified by a chemical transformation. Examples include but are notlimited to hydrolysis of ester or cyano groups in R^(I). Suitableconditions for carrying out the transformations in Scheme 3 areexemplified in Example 3. Those skilled in the art will realize thatalternate synthetic methods may be employed to accomplish the reactionsin Scheme 3.

Those having skill in the art will recognize that the starting materialsmay be varied and additional steps employed to produce compoundsencompassed by the present invention, as demonstrated by the followingexamples.

The following examples illustrate the general procedures for thepreparation of compounds of the invention using the reactions outlinedabove in Schemes 1-3. These examples are not to be construed as limitingthe invention in scope or spirit to the specific procedures andcompounds described in them.

Example 1 General Procedure for the Preparation of SubstitutedImidazoles as Outlined in Scheme 1 Preparation of(2-Chloro-3,4-dimethoxyphenyl)-N-({1-[(2-chlorophenyl)methyl]-4,5-dimethylimidazol-2-yl}methyl)-N-(3-methylbutyl)carboxamide

To a solution of 4.89 g (0.027 mol) of 4,5-dimethylimidazolehydrobromide and 5.7 g (0.028 mol) of 2-chlorobenzyl bromide in 20 ml ofDMF is added 6 ml of 50% potassium hydroxide aqueous solution dropwise.Then the reaction mixture is stirred at RT under nitrogen overnight. Thereaction mixture is poured into ether (100 ml)/ water (50 ml). The etherlayer is separated, washed with water (10 ml×2), dried over anhydroussodium sulfate and evaporated in vacuo. The raw material is subjected tochromatography on silica gel using dichloromethane-methanol (10:1) aseluent to give 2.67 g (44%) of 1-(2′-chlorobenzyl)-4,5-dimethylimidazoleas a pale yellow oil. MS m/z (M⁺+1) 221; ¹H-NMR 400 MHz(δ, CDCl₃): 2.00(3H, s), 2.20 (3H, s), 5.07 (2H, s), 6.59 (1H, dd, J=9.2, 2 Hz), 7.17(1H, td, J=8, 1.2 Hz), 7.23 (1H, td, J=8, 1.6 Hz), 7.38 (2H, dd, J=7.2,1.6 Hz) ppm.

To a solution of 10 ml of glacial acetic acid and 10 ml of 37%formaldehyde is added 2.67 g (0.012 mol) of1-(2′-chlorobenzyl)-4,5-dimethylimidazole. The mixture is stirred andheated in a sealed tube at 125-130° C. (oil bath temperature) overnight.After cooling, the solvent is evaporated in vacuo. The residue issubjected to chromatography on silica gel using dichloromethane-methanol(10:1) as eluent to give 2.39 g (79%) of1-(2′-chlorobenzyl)-4,5-dimethyl-2-hydroxymethylimidazole as colorlesspowder. MS m/z (M⁺+1) 251; ¹H-NMR 400 MHz(δ, CDCl₃): 1.94 (3H, s), 2.11(3H, s), 4.53 (2H, s), 5.26 (2H, s), 6.42 (1H, dd, J=8, 1.2 Hz),7.14(1H, td, J=8, 1.2Hz), 7.21 (1H, td, J=7.4, 1.6 Hz), 7.39 (1H, dd,J=8, 1.2 Hz) ppm.

To 3 ml of thionyl chloride is added 2.39 g (9.5 mmol) of1-(2′-chlorobenzyl)-4,5-dimethyl-2-hydroxymethyl-imidazole. The mixtureis heated at 50° C. for about 5 min., and the thionyl chloride isevaporated in vacuo. The residue is dissolved in 10 ml ofdichloromethane, then evaporated in vacuo. This is repeated twice togive 1-(2′-chlorobenzyl)-4,5-dimethyl-2-chloromethylimidazole as a creamcolored foam which is used in next step without further purification.

To a solution of 7 ml (60 mmol) of isoamylamine in 3 ml of acetonitrileis added slowly a solution of1-(2′-chlorobenzyl)-4,5-dimethyl-2-chloromethylimidazole in 10 ml ofacetonitrile followed by added 1.5 g (10.8 mmol) of potassium carbonatepowder. The reaction mixture is stirred overnight at room temperatureunder nitrogen and excess isoamylamine is evaporated in vacuo. Theresidue is dissolved in 50 ml of ethyl acetate and 25 ml of water. Theethyl acetate layer is separated, washed with brine, dried overanhydrous sodium sulfate and evaporated in vacuo. The crude product ispurified by preparative TLC [silica gel, chloroform-methanol-ammoniumhydroxide (90:10:1)] to give 1.39 g (46%) ofN-[(4,5-dimethylimidazol-2-yl)methyl]-(3-methylbutyl)amine as a yellowoil. MS m/z (M⁺+1) 320; ¹H-NMR 400 MHz(δ, CDCl₃): 0.81 (6H, d, J=6.4Hz), 1.25 (2H, m), 1.51 (1H, m), 1.96 (3H, s), 2.17 (3H, s), 2.56 (2H,m), 3.68 (2H, s), 5.21 (2H, s), 6.39 (1H, d, J=7.6 Hz), 7.13 (1H, m),7.19 (1H, m), 7.37 (1H, m) ppm.

To a solution of 210 mg (0.66 mmol) ofN-[(4,5-dimethylimidazol-2-yl)methyl]-(3-methylbutyl)amine in 5 ml ofchloroform (stabilized with amylenes) is added 170 mg (0.84 mmol) of2-chloro-3,4-dimethoxybenzoyl chloride and 1 ml of triethylamine. Thereaction mixture is stirred at RT under nitrogen overnight andevaporated in vacuo. The residue is dissolved in 20 ml of ethyl acetateand 10 ml of water. The ethyl acetate layer is separated, washed withbrine (5 ml×2), dried over anhydrous sodium sulfate, and the solvent isevaporated in vacuo. The crude product is purified by preparative TLC[silica gel, chloroform-methanol-ammonia hydroxide (95:4.5:0.5)] to givethe title compound as a colorless oil. MS m/z (M⁺+1) 518; ¹H-NMR 400MHz(δ, CDCl₃): 0.61 and 0.88 (6H, d, J=6 Hz, the ratio of two peaks is4/1), 1.26 (2H, m), 1.36 (1H, m), 1.89 and 1.94 (3H, s, the ratio of twopeaks is 1/4), 2.14 and 2.17 (3H, s, the ratio of two peaks is 1/4),3.04 (2H, br), 3.74 and 3.80 (3H, s, the ratio of two peaks is 1/4),3.78 and 3.82 (3H, s, the ratio of two peaks is 1/4), 4.72, 4.84, 5.17,5.47 (4H, 4 br), 6.30 (2H, d, J=8.4 Hz), 6.67 (1H, d, J=8.8 Hz), 7.15(1H, td, J=7.2, 1.2 Hz), 7.21 (1H. td, J=7.2, 1.2 Hz), 7.38 (1H, dd,J=7.2, 1.2 Hz) ppm.

Example 2 General Procedure for the Preparation of SubstitutedImidazoles as Outlined in Scheme 2 Preparation of(2-Chloro-3,4-dimethoxyphenyl)-N-({1-[(2-methoxyphenyl)methyl]-4,5-dimethylimidazol-2-yl}methyl)-N-(3-methylbutyl)carboxamide

A mixture of 3.35 g (27 mmol) of 4,5-dimethyl-2-imidazolecarboxaldehyde,9.0 mL (77 mmol) of isoamylamine, 200 mL of ethanol, and 0.20 g ofplatinum dioxide is hydrogenated under 50 psi of pressure at 22° C. for24 h. The solution is filtered, and the volatiles are evaporated underreduced pressure to give 5.17 g (98%) ofN-[(4,5-dimethylimidazol-2-yl)methyl]-(3-methylbutyl)amine. Mass Specm/z (M⁺+1) 196.

A mixture of 4.50 g (20 mmol) of 2-chloro-3,4-dimethoxybenzoic acid, 5mL of chloroform, 0.2 mL of pyridine, and 5.8 mL (80 mmol) of thionylchloride is stirred at 40° C. for 1 h. The volatiles are thoroughlyevaporated. A solution of the residue in 10 mL of chloroform is addeddropwise to a solution of 2.73 g (14 mmol) ofN-[(4,5-dimethylimidazol-2-yl)methyl]-3-methylbutylamine in 20 mL ofanhydrous pyridine stirred under nitrogen at −20° C. The obtainedmixture is allowed to warm up slowly, and it is stirred then at 20° C.for 20 h.

The reaction mixture is poured into 50 mL of water and extracted with 50mL of chloroform. The extract is washed with 50 mL of 5% NaCO₃, and thesolvent is evaporated. The residue is dissolved in 20 mL of ethanol,treated with 2 mL of 10N NaOH, and stirred at 60° C. for 1 h. Themixture is poured into 50 mL of 5% NaCO₃ and extracted with 50 mL ofchloroform. The solvent is evaporated under reduced pressure. The crudeproduct is purified by column chromatography on 100 g of silica gelusing chloroform-methanol—28% ammonium hydroxide (95:4.5:0.5, v/v/v) asan eluent to give 2.42 g (44%) of(2-chloro-3,4-dimethoxyphenyl)-N-[(4,5-dimethylimidazol-2-yl)methyl]-N-(3-methylbutyl)carboxamide.Mass Spec m/z (M⁺+1) 394.

A mixture of 0.74 g (1.9 mmol) of(2-chloro-3,4-dimethoxyphenyl)-N-(3,4-dimethylimidazol-2-yl)methyl-N-(3-methylbutyl)carboxamide,0.94 g (6.0 mmol) of 2-methoxybenzyl chloride, 10 mL ofdimethylformamide and 0.63 mL (8.0 mmol) of 50% KOH is stirredvigorously under nitrogen at 40° C. for 20 h. The reaction mixture ispoured into 100 mL of water and extracted with 50 mL of chloroform. Theextract is washed with 100 mL of water, and the solvent is evaporatedunder reduced pressure. The residue is diluted with 50 mL of xylenes,and the volatiles are thoroughly evaporated under reduced pressure.Column chromatography of the residue on 30 g of silica gel usingchloroform-diethyl ether (98:2, v/v) as an eluent afforded 646 mg (67%)of the title compound as a cream colored foam. Mass Spec m/z (M++1) 514.

Example 3 General Procedure for the Preparation of SubstitutedImidazoles as Outlined in Scheme 3

Preparation of(2-Chloro-3,4-dimethoxyphenyl)-N-({1-[(2-hydroxyphenyl)methyl]4,5-dimethylimidazol-2-yl}methyl)-N-(3-methylbutyl)carboxamido

A mixture of 1.89 g (4.8 mmol) of(2-chloro-3,4-dimethoxyphenyl)-N-(3,4-dimethylimidazol-2-yl)methyl-N-(3-methylbutyl)carboxamide,0.74 g (6.0 mmol) of 2-hydroxybenzyl alcohol, 50 mL of toluene, 0.10 gof p-toluenesulfonic acid monohydrate, and 15 g of molecular sieves 5Ais gently stirred and heated under nitrogen at 100° C. for 24 h. Anotherportion of 2-hydroxybenzyl alcohol (0.37 g, 3.0 mmol) is added, andheating at 100° C. is continued for additional 24 h. The molecularsieves are filtered off and washed with 20 mL of ethyl acetate-methanol(4:1). The filtrate and washings are combined, and the solvent isevaporated under reduced pressure. The crude material is purified bycolumn chromatography on 75 g of silica gel usingchloroform-methanol-acetic acid (96:3:1) as an eluent to give 1.74 g(72%) of the title compound. Mass Spec m/z (M⁺+1) 500.

Preparation of Ethyl{2-[(2-{[(2-chloro-3,4-dimethoxyphenyl)-N-(3-methylbutyl)carbonylamino]methyl}-4,5-dimethylimidazol-1-yl)methyl]phenoxy}acetate

A mixture of 0.55 g (1.1 mmol) of(2-chloro-3,4-dimethoxyphenyl)-N-({1-[(2-hydroxyphenyl)-methyl]4,5-dimethylimidazol-2-yl}methyl)-N-(3-methylbutyl)carboxamide, 0.24mL(2.2 mmol) of ethyl bromoacetate, 0.69 g (5.0 mmol) of K₂CO_(3,) and 5mL of anhydrous dimethylformamide is stirred under nitrogen at 22° C.for 20 h. The reaction mixture is poured onto 50 g of crushed ice,acidified to pH 6 with 1M HCl, and extracted with hexanes-ethyl acetate(25 mL of each). The extract is washed with water (2×50 mL), dried overMgSO_(4,) and the solvents are evaporated under reduced pressure. Theresidue is purified by column chromatography on 30 g of silica gel usingethyl acetate as an eluent to give 0.51 g (79%) of the title compound.Mass Spec m/z (M⁺+1) 586.

Preparation of{2-[(2-{[(2-Chloro-3,4-dimethoxyphenyl)-N-(3-methylbutyl)carbonylamino]methyl}-4,5-dimethylimidazol-1-yl)methyl]phenoxy}aceticacid

A solution of 58 mg of{2-[(2-{[(2-chloro-3,4-dimethoxyphenyl)-N-(3-methylbutyl)carbonylamino]methyl}-4,5-dimethylimidazol-1-yl)methyl]phenoxy}acetatein 2 mL of 5N HCl is heated under reflux for 15 min. The volatiles areevaporated under reduced pressure, and the residue is dried in a vacuumoven at 90° C. to give 59 mg of the title compound as the hydrochloridesalt. Mass Spec m/z (M⁺+1) 558.

Example 4 Alternate Alkylation Conditions for Substituted ImidazolesPrepared in Scheme 2

Preparation of (2-Chloro-3,4-dimethoxyphenyl)-N-({1-[(2-cyanophenyl)methyl]4,5-dimethylimidazol-2-yl}methyl)-N-(3-methylbutyl)carboxamido

A mixture of 197 mg (0.50 mmol) of(2-chloro-3,4-dimethoxyphenyl)-N-(3,4-dimethylimidazol-2-yl)methyl-N-(3-methylbutyl)carboxamide,147 mg (0.75 mmol) of α-bromo-o-tolunitrile, 3 mL of DMF, and 415 mg (3mmol) of K₂CO₃ is stirred under nitrogen at 22° C. for 24 h. Thereaction mixture is poured into 30 mL of water and extracted with 30 mLof diethyl ether. The extract is washed with water (2×20 mL), and thesolvent is evaporated. The residue is dissolved in 20 mL of xylenes, andthe volatiles are thoroughly evaporated in vacuo. The crude product ispurified by column chromatography on 24 g of silica gel usingchloroform-diethyl ether (85:15) as an eluent to give 181 mg (71% yield)of the title compound. Mass Spec m/z (M⁺+1) 509.

Example 5 Preparation of2-{2-{[(2-Chloro-3,4-dimethoxyphenyl)-N-(3-methylbutyl)carbonylamino}methyl]-4,5-dimethylimidazol-1-yl)methyl}benzoicacid

A mixture of 140 mg (0.27 mmol) of(2-Chloro-3,4-dimethoxyphenyl)-N-({1-[(2-cyanophenyl)methyl]4,5-dimethylimidazol-2-yl}methyl)-N-(3-methylbutyl)carboxamide, 2.0 mLof ethanol and 1.0 mL of 50% KOH is stirred under nitrogen at 80° C. for18 h. The reaction mixture is poured into 30 g of ice-water, acidifiedto pH 5 with 1M HCl, and extracted with 20 mL of ethyl acetate. Theextract is washed with 10 mL of water, and the solvent is evaporatedunder reduced pressure. The residue is triturated with 2 mL of acetone,and the crystals are separated by decantation to give 112 mg (78%) ofthe title compound. Mass Spec m/z (M⁺+1) 528.

Example 6 Preparation of(2-Chloro-3,4-dimethoxyphenyl)-N-({1-[(2-[cyanomethoxyl]-phenyl)methyl]4,5-dimethylimidazol-2-yl}methyl)-N-(3-methylbutyl)carboxamide.

A mixture of 250 mg (0.50 mmol) of(2-chloro-3,4-dimethoxyphenyl)-N-(4,5-dimethylimidazol-2-yl)methyl-N-(3-methylbutyl)carboxamide,52 μL of chloroacetonitrile (0.75 mmol), 276 mg (2.0 mmol) of K₂CO_(3,)and 3 mL of anhydrous DMF is stirred under nitrogen at 22° C. for 24 hand poured into 10% NaCl. The mixture is extracted with 20 mL of ethylacetate. The extract is concentrated under reduced pressure, dilutedwith 20 mL of xylenes, and the volatiles are thoroughly evaporated. Thecrude product is purified by chromatography on 30 g of silica gel usingchloroform—methanol—28% ammonium hydroxide (98:1.8:0.2, v/v/v) forelution to afford 113 mg (42% yield) of the title compound. Mass Specm/z (M⁺+1) 539.

Using the above procedures, the following compounds were preparedaccording to Schemes 1, 2 and 3:

(a)(2-Chloro-3,4-dimethoxyphenyl)-N-{[1-benzyl-4,5-dimethylimidazol-2-yl]methyl}-N-(3-methylbutyl)carboxamide. Mass Spec m/z (M⁺+1) 484.

(b)(2-Chloro-3,4-dimethoxyphenyl-N-({4,5-dimethyl-1-[(2-methylphenyl)methyl]}imidazol-2-yl}methyl-N-(3-methylbutyl)carboxamide.Mass Spec m/z (M⁺+1) 498.

(c)(2-Chloro-3,4-dimethoxyphenyl-N-[(4,5-dimethyl-1-{[2-(trifluoromethyl)phenyl]methyl}imidazol-2-yl)methyl]-N-(3-methylbutyl)carboxamide.Mass Spec m/z (M⁺+1) 552.

(d)N-{[4,5-Dichloro-1-benzylimidazol-2-yl]methyl}(2-chloro-3,4-dimethoxyphenyl)-N-(3-methylbutyl)carboxamide.Mass Spec m/z (M⁺+1) 524.

(e)N-({4,5-Dichloro-1-[(2-chlorophenyl)methyl]imidazol-2-yl}methyl)(2-chloro-3,4-dimethoxyphenyl)-N-(3-methylbutyl)carboxamide.Mass Spec m/z (M⁺+1) 560.

(f)N-({4,5-Dichloro-1-[(2-methylphenyl)methyl]imidazol-2-yl]methyl)(2-chloro-3,4-dimethoxyphenyl)-N-(3-methylbutyl)carboxamide.Mass Spec m/z (M⁺+1) 540.

(g)(2-Chloro-3,4-dimethoxyphenyl)-N-{3,4-diethyl-1-[(pyridin-2-yl)methyl]imidazol-2-yl}methyl-N(3-methylbutyl)carboxamide. Mass Spec m/z (M⁺+1) 513.

(h)2-Chloro-3,4-dimethoxyphenyl)-N-{3,4-dimethyl-1-[quinolin-2-yl)methyl]imidazol-2-yl}methyl-N-(3-methylbutyl)carboxamide.Mass Spec m/z (M⁺+1) 535.

(i)(2-Chloro-3,4-dimethoxyphenyl)-N-{4,5-diethyl-1-[(5-ethyl-2-methoxyphenyl)methyl]imidazol-2-yl}methyl-N-(3-methylbutyl)carboxamide.Mass Spec m/z(M⁺+1)570.

(j) (2-Chloro-3,4-dimethoxyphenyl)-N-({1-[(5-bromo-2-hydzoxyphenyl)methyl]4,5-dimethylimidazol-2-yl}methyl-N-(3-methylbutyl)carboxamide. Mass Spec m/z (M³⁰+1) 579.

(k)(2-Chloro-3,4-dimethoxyphenyl)-N-{3,4-dimethyl-1-[(5-chloro-2-hydroxyphenyl)methyl]imidazol-2-yl}methyl-N-(3-methylbutyl)carboxamide. Mass Spec m/z (M⁺+1) 534.

(l)(2-Chloro-3,4-dimethoxyphenyl)-N-({3-[(2-chlorophenyl)methyl](3,4,5,6,7-pentahydrobenzimidazol-2-yl)}methyl)-N-(3-methylbutyl)carboxamide.Mass Spec m/z (M⁺+1) 544.

Example 7 Additional Compounds of the Invention

Additional Compounds of the invention which may be prepared by themethods outlined in Reaction Schemes 1, 2, and 3 are shown in Table I.

Ex # R10 R11 R12 R13 R14 R15 R16 1

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Example 8 Ligand Binding Assay on Sf9 cell membranes expressing the BK-2receptor

This assay is used to determine the high affinity of compounds of thisinvention for the BK-2 (bradykinin B₂) receptor.

Binding Buffer: 50 mM Tris 7.0 (cold), 0.14 grams per liter bacitracin(approx. 50,000 units of activity/liter, lot# 103746 from Amersham), and10⁻⁶ M captopril. Captopril is purchased from Sigma C-4042, 2.17 mg in10 ml of milli-Q water produces a 10⁻³ M stock. Stock can be stored for3 weeks in the refrigerator. 1.0 ml of stock per liter buffer=10⁻⁶ Mfinal concentration.

Ligand Preparation: 0.25 nM ³H-Bradykinin is used. 10 μl of stock+100 mlof binding buffer gives approximately 600 cpm/5 μl aliquot.

Non-Specific Preparation: NS binding is defined by unlabeled bradykininat 1 μM final concentration. Aliquots are stored at −20 ° C. in 0.5% BSAat a concentration of 10⁻³ M. Aliquots are then diluted 1:100 for anintermediate concentration of 10⁻⁵ M.

Baculovirus-infected Sf9 cells expressing recombinant human bradykininB₂ receptors are harvested 48 hours post infection via centrifugation at3000×g. Cells are washed with ice-cold PBS and stored at −70° C. untilneeded. Frozen cell pellets are resuspended in ice cold Washing Buffer(50 mM Tris pH 7.0) and homogenized via POLYTRON for 30 seconds atsetting 5. Membranes are centrifuged at 40,000×g for 10 min. Pellets areresuspended in Washing Buffer with the aid of a polytron and centrifugedagain. Membranes are resuspended in binding buffer at a concentration of133 μg/ml. This corresponds to 20 μg of protein per 150 μl.

When measuring non-specific binding, incubations contain 150 μl of Sf9cell membranes prepared as described above, 50 μl ³H-Bradykinin (0.25nM), 25 μl unlabeled bradykinin at 1 μM final concentration and 2 μlDMSO. Incubations for determining test compound binding contain 175 μlof Sf9 cell membranes, 50 μl ³H-Bradykinin (0.25 nM), and test compoundin 2 μl DMSO. The concentration of the test compound is generally 1 μMfor displacement studies. The binding reaction components are incubatedfor 2 hrs at 4° C. in Falcon U bottom plates. Plates are harvested onthe microbeta harvester onto 0.5% PEI pretreated unifilters. Afterharvesting, the filters are dried overnight. 17 μl of beta-scint isadded to each well before the unifilters are counted in the microbetacounters. Data are collected in duplicate determinations, averaged and %inhibition of total specific binding is calculated. Total SpecificBinding=Total−Nonspecific. In some cases, the amounts of unlabeled drugis varied and total displacement curves of binding are carried out. Dataare converted to a form for the calculation of IC₅₀ and Hill Coefficient(nH). Ki's are subsequently determined by the Cheng-Prusoff equation(Cheng, Y. C.; Prusoff, W. C. Biochem. Pharmacol. 1972, 22, 3099-3108).In the described assay, preferred compounds of the invention have Ki'sof less than 1 μM, more preferred compounds of the invention exhibit Kivalues of less than 500 nM and even more preferred compounds of theinvention exhibit Ki values of less than 100 nM.

Example 9 BK-2 Receptor Mediated Calcium Mobilization

The agonist and antagonist properties of the compounds of the inventioncan be evaluated by the following assay.

CHO cells stably expressing the BK-2 receptor are grown in Ham's F-12media supplemented with 250 μg/ml G418, 1 μg/ml tetracycline, 7 μg/mlpuromycin, 10% fetal bovine serum and 25 mM Hepes, pH=7.4. Forty eighthours prior to assay, the cell growth media is replaced with anothermedium that does not contain the tetracycline. Twenty four hours priorto experiment sodium butyrate is added to a final concentration of 10mM. On the day of assay, cells, grown to 70-90% confluency in 96-wellplates, are washed with Krebs-Ringer buffer (25 mM HEPES, 5 mM KCl, 0.96mM NaH₂PO₄, 1 mM MgSO₄, 2 mM CaCl₂, 5 mM glucose, and 1 mM probenecid,pH 7.4) and are then incubated for 1-2 hours in the above buffersupplemented with Fluo3-AM (2.5 ñ 10 (g/ml; Teflabs) at 37° C. in anenvironment containing 5% CO₂. The wells are then washed twice withKrebs-Ringers buffer. Agonist-induced (bradykinin) calcium mobilizationis monitored using either Fluoroskan Ascent (Labsystems) or FLIPR(Molecular Devices) instruments. The agonists, either bradykinin or drugcandidates, are added to the cells and fluorescence responses arecontinuously recorded for up to 5 min. For the examination of antagonistdrug candidates, compounds, at a concentration of 1 μM in DMSO, arepreincubated with the cells for up to 30 minutes prior to administrationof the bradykinin agonist. Bradykinin agonist is generally applied at aconcentration sufficient to induce 50% maximal activity. Responses arerecorded for up to 5 min. Kaleidagraph software (Synergy Software,Reading, Pa.) is utilized to fit the data to the equationy=a*(1/(1+(b/x)c)) to determine the EC₅₀ value or IC₅₀ value for theresponse. In this equation, y is the maximum fluorescence signal, x isthe concentration of the agonist or antagonist, a is the Emax, bcorresponds to the EC₅₀ or IC₅₀ value, and, finally, c is the Hillcoefficient.

Example 10 Preparation of Radiolabeled Probe Compounds of the Invention

The compounds of the invention are prepared as radiolabeled probes bycarrying out their synthesis using precursors comprising at least oneatom that is a radioisotope. The radioisotope is preferably selectedfrom of at least one of carbon (preferably ¹⁴C), hydrogen (preferably³H), sulfur (preferably ³⁵S), or iodine (preferably ¹²⁵I). Suchradiolabeled probes are conveniently synthesized by a radioisotopesupplier specializing in custom synthesis of radiolabeled probecompounds. Such suppliers include Amersham Corporation, ArlingtonHeights, Ill.; Cambridge Isotope Laboratories, Inc. Andover, Mass.; SRIInternational, Menlo Park, Calif.; Wizard Laboratories, West Sacramento,Calif.; ChemSyn Laboratories, Lexena, Kans.; American RadiolabeledChemicals, Inc., St. Louis, Mo.; and Moravek Biochemicals Inc., Brea,Calif.

Tritium labeled probe compounds are also conveniently preparedcatalytically via platinum-catalyzed exchange in tritiated acetic acid,acid-catalyzed exchange in tritiated trifluoroacetic acid, orheterogeneous-catalyzed exchange with tritium gas. Such preparations arealso conveniently carried out as a custom radiolabeling by any of thesuppliers listed in the preceding paragraph using the compound of theinvention as substrate. In addition, certain precursors may be subjectedto tritium-halogen exchange with tritium gas, tritium gas reduction ofunsaturated bonds, or reduction using sodium borotritide, asappropriate.

Example 11 Use of Compounds of the Invention as Probes for BK-2Receptors in Cultured Cells and Tissue Samples

The presence of BK-2 receptors in cultured cells or tissue samples maybe ascertained by the procedures described by Hall and Morton in thechapter entitled “Immunopharmacology of the Bradykinin Receptor” of TheHandbook of Immunopharmacology—The Kinin Systems (1997) Academic Press,S. C. Fanner, editor, using radiolabeled compounds of the inventionprepared as described in the preceding Example 9.

The invention and the manner and process of making and using it, are nowdescribed in such full, clear, concise and exact terms as to enable anyperson skilled in the art to which it pertains, to make and use thesame. It is to be understood that the foregoing describes preferredembodiments of the present invention and that modifications may be madetherein without departing from the spirit or scope of the presentinvention as set forth in the claims. To particularly point out anddistinctly claim the subject matter regarded as invention, the followingclaims conclude this specification.

What is claimed is:
 1. A compound of the formula

or a pharmaceutically acceptable salt, prodrug, or solvate thereof, wherein: R₁ is arylalkyl which is optionally substituted directly or through a O(CH₂)_(n) linker (where n=1, 2, 3 or 4) with up to three substituents independently selected from: (i) halogen nitro, trifluoromethyl, trifluoromethoxy, cyano, hydroxyl, C₁-C₆ alkyl, amino, C₁-C₆ alkoxy, aminomethyl, mono or di(C₁-C₆)alkylamino, mono or dialkylaminomethyl, (wherein each alkyl is independently lower (C₁-C₆) alkyl), (ii) C₁-C₆alkoxyNR₈R_(9,) NR₈R_(9,) NR₈COR_(9,) CONR₈R_(9,) wherein R₈ and R₉ are the same or different and represent hydrogen, straight or branched chain lower alkyl, (iii) O(CH₂)_(n)CO₂R_(A) wherein n=1,2,3,4, COR_(A,) and CO₂R_(A,) wherein R_(A) represents hydrogen or straight chain lower alkyl, (iv) SO₂R_(A,) NHSO₂R_(A,) SO₂NHR_(A,) SO₂NHCOR_(A,) and CONHSO₂R_(A,) wherein R_(A) represents hydrogen or straight chain lower alkyl, with the proviso that R₁ may not be 3-Fluorobenzyl; R₂ and R₃ are the same or different and represent (i) halogen, trifluoromethyl, trifluoromethoxy, lower alkoxy having 1-6 carbon atoms, lower alkyl, amino methyl, mono or dialkylaminomethyl, wherein each alkyl is independently lower (C₁-C₆) alkyl, (ii) C₁-C₆alkoxyNR₈′R₉′, NR₈′R₉′, CONR₈′R₉′, NR₈′COR₉′, wherein R₈′ and R₉′ are the same or different and represent hydrogen or straight or branched chain lower alkyl, (iii) O(CH₂)_(n)CO₂R_(A)′ where n=1,2,3,4, COR_(A)′, or CO₂R_(A)′, wherein R_(A)′ represents hydrogen or straight chain lower alkyl; R₄ represents straight or branched chain lower alkyl; R₅ represents halogen or trifluoromethyl; R_(6,) R₇ and R₇′ are the same or different and represent (i) hydrogen, trifluoromethyl, trifluoromethoxy, nitrile, C₁-C₁₀ alkyl, C₁-C₁₀ alkoxy (with the proviso that R_(6,) R_(7,) or R₇′ may not be C₁-C₁₀ alkoxy when located ortho to Y), C₁-C₆alkylthio, halogen, aminomethyl, di(C₁-C₆)alkylamino, mono or diC₁-C₆alkylaminomethyl, or (ii) C₁-C₆ alkoxyaminoalkyl where the amino is mono or disubstituted with straight or branched chain lower alkyl; (iii) or any two adjacent R_(6,) R₇ or R₇′ may be joined to form a 5 to 7 membered carbocyclic ring; or R₅ and R₆ are joined to form a 6 membered carbocyclic aromatic ring which is optionally substituted with up to four substituents selected from: (i) halogen, nitro, trifluoromethyl, cyano, hydroxyl, C₁-C₆ alkyl, amino, C₁-C₆ alkoxy, aminomethyl, alkylaminomethyl, mono or di(C₁-C₆)alkylamino, mono or dialkylaminomethyl, wherein each alkyl is independently lower (C₁-C₆) alkyl, (ii) C₁-C6alkoxyNR₈″R₉″, NR₈″R₉″, CONR₈″R₉″, NR₈″COR₉″, where R₈″ and R₉″ are the same or different and represent hydrogen or straight or branched chain lower alkyl, (iii) O(CH₂)_(n)CO₂R_(A)″ where n=1,2,3,4, COR_(A)″, or CO₂R_(A)″, wherein R_(A)″ represents hydrogen or straight chain lower alkyl; and R₇ and R₇′ are as defined above; and Y represents a bond or CH_(2,) when Y=CH₂ it may be mono or disubstituted with a straight or branched chain lower alkyl, or straight or branched chain lower alkoxy having 1-6 carbon atoms.
 2. A compound of the formula

or a pharmaceutically acceptable salt, prodrug, or solvate thereof, wherein: R₁ is benzyl, each of which is optionally substituted directly or through a O(CH₂)_(n) linker (where n=1,2,3 or 4) with up to three substituents independently selected from: (i) halogen (with the proviso that R₁ may not be 3-Fluorobenzyl), nitro, trifluoromethyl, trifluoromethoxy, cyano, hydroxyl, C₁-C₆ alkyl, amino, C₁-C₆ alkoxy, aminomethyl, mono or di(C₁-C₆)alkylamino, mono or dialkylaminomethyl, (wherein each alkyl is independently lower (C₁-C₆) alkyl), (ii) C₁-C₆alkoxyNR₈R_(9,) NR₈R_(9,) NR₈COR_(9,) CONR₈R_(9,) wherein R₈ and R₉ are the same or different and represent hydrogen, straight or branched chain lower alkyl, (iii) O(CH₂)_(n)CO₂R_(A) wherein n=1,2,3,4, COR_(A,) and CO₂R_(A,) wherein R_(A) represents hydrogen or straight chain lower alkyl, (iv) SO₂R_(A,) NHSO₂R_(A,) SO₂NHR_(A,) SO₂NHCOR_(A,) and CONHSO₂R_(A,) wherein R_(A) represents hydrogen or straight chain lower alkyl, R₂ and R₃ are the same or different and represent (i) halogen, trifluoromethyl, trifluoromethoxy, lower alkoxy having 1-6 carbon atoms, lower alkyl, amino methyl, mono or dialkylaminomethyl, wherein each alkyl is independently lower (C₁-C₆) alkyl, (ii) C₁-C₆alkoxyNR₈′R₉′, NR₈′R₉′, CONR₈′R₉′, NR₈′COR₉′, wherein R₈′ and R₉′ are the same or different and represent hydrogen or straight or branched chain lower alkyl, (iii) O(CH₂)_(n)CO₂R_(A)′ where n=1,2,3,4, COR_(A)′, or CO₂R_(A)′, wherein R_(A)′ represents hydrogen or straight chain lower alkyl; or R₄ represents straight or branched chain lower alkyl; R₅ represents halogen or trifluoromethyl; R_(6,) R₇ and R₇′ are the same or different and represent (i) hydrogen, trifluoromethyl, trifluoromethoxy, nitrile, C₁-C₁₀ alkyl, C₁-C₁₀ alkoxy (with the proviso that R_(6,) R_(7,) or R₇′ may not be C_(l)-C₁₀ alkoxy when located ortho to Y), C₁-C₆alkylthio, halogen, aminomethyl, di(C₁-C₆)alkylamino, mono or diC₁-C₆alkylaminomethyl, or (ii) C₁-C₆ alkoxyaminoalkyl where the amino is mono or disubstituted with straight or branched chain lower alkyl; (iii) or any two adjacent R_(6,) R₇ or R₇′ may be joined to form a 5 to 7 membered carbocyclic ring; and Y represents a bond or CH_(2,) when Y=CH₂ it may be mono or disubstituted with a straight or branched chain lower alkyl, or straight or branched chain lower alkoxy having 1-6 carbon atoms.
 3. A compound of the formula:

or a pharmaceutically acceptable salt, prodrug, or solvate thereof, wherein: R₁ is benzyl which is optionally substituted directly or through a O(CH₂)_(n) linker (where n=1, 2, 3 or 4) with up to three substituents independently selected from: (i) halogen (with the proviso that R₁ may not be 3-Fluorobenzyl), nitro, trifluoromethyl, trifluoromethoxy, cyano, hydroxyl, C₁-C₆ alkyl, amino, C₁-C₆ alkoxy, aminomethyl, mono or di(C₁-C₆)alkylamino, mono or dialkylaminomethyl, (wherein each alkyl is independently lower (C₁-C₆) alkyl), (ii) C₁-C₆alkoxyNR₈R_(9,) NR₈R_(9,) NR₈COR_(9,) CONR₈R_(9,) wherein R₈ and R₉ are the same or different and represent hydrogen, straight or branched chain lower alkyl, (iii) O(CH₂)_(n)CO₂R_(A) wherein n=1,2,3,4, COR_(A), and CO₂R_(A,) wherein R_(A) represents hydrogen or straight chain lower alkyl, (iv) SO₂R_(A), NHSO₂R_(A), SO₂NHR_(A), SO₂NHCOR_(A), CONHSO₂R_(A), wherein R_(A) represents hydrogen or straight chain lower alkyl; R₂ and R₃ are the same or different and represent (i) halogen, trifluoromethyl, trifluoromethoxy, lower alkoxy having 1-6 carbon atoms, lower alkyl, amino methyl, mono or dialkylaminomethyl, wherein each alkyl is independently lower (C₁-C₆) alkyl, (ii) C₁-C₆alkoxyNR₈′R₉′, NR₈′R₉′, CONR₈′R₉′, NR₈′COR₉′, wherein R₈′ and R₉′ are the same or different and represent hydrogen or straight or branched chain lower alkyl, (iii) O(CH₂)_(n)CO₂R_(A)′ where n=1,2,3,4, COR_(A)′, or CO₂R_(A)′, wherein R_(A)′ represents hydrogen or straight chain lower alkyl; R₄ represents straight or branched chain lower alkyl; R₅ is part of an aromatic ring formed with R_(6;) R₆ is part of a 6 membered carbocyclic aromatic ring formed with R₅ which is optionally substituted with up to four substituents selected from: (i) halogen, nitro, trifluoromethyl, cyano, hydroxyl, C₁-C₆ alkyl, amino, C₁-C₆ alkoxy, aminomethyl, alkylaminomethyl, mono or di(C₁-C₆)alkylamino, mono or dialkylaminomethyl, wherein each alkyl is independently lower (C₁-C₆) alkyl, (ii) C₁-C₆alkoxyNR₈″R₉″, NR₈″R₉″, CONR₈″R₉″, NR₈″COR₉″, where R₈″ and R₉″ are the same or different and represent hydrogen or straight or branched chain lower alkyl, (iii) O(CH₂)_(n)CO₂R_(A)″ where n=1,2,3,4, COR_(A)″, or CO₂R_(A)″, wherein R_(A)″ represents hydrogen or straight chain lower alkyl; and R₇ and R₇′ represent hydrogen, trifluoromethyl, trifluoromethoxy, nitrile, C₁-C₁₀ alkyl, C₁-C₁₀ alkoxy (with the proviso that R₆ R_(7,) or R₇′ may not be C₁-C₁₀ alkoxy when located ortho to Y), C₁-C₆alkylthio, halogen, aminomethyl, di(C₁-C₆)alkylamino, mono or diC₁-C₆alkylaminomethyl, or C₁-C₆alkoxyaminoalkyl where the amino is mono or disubstituted with straight or branched chain lower alkyl; and Y represents a bond or CH_(2,) when Y=CH₂ it may be mono or disubstituted with a straight or branched chain lower alkyl, or straight or branched chain lower alkoxy having 1-6 carbon atoms.
 4. A compound according to claim 2 of the formula

wherein R₁ and R₄ are as defined in claim
 2. 5. A compound according to claim 4 wherein R₄ is isoamyl or n-pentyl.
 6. A compound according to claim 2 of the formula

wherein R₁ and R₄ are as defined in claim
 2. 7. A compound according to claim 6 wherein R₄ is isoamyl or n-pentyl.
 8. A compound according to claim 1, which is (2-Chloro-3,4-dimethoxyphenyl)-N-({1-[(2-chlorophenyl)methyl]-4,5-dimethylimidazol-2-yl}methyl)-N-(3-methylbutyl)carboxamide.
 9. A compound according to claim 1, which is (2-Chloro-3,4-dimethoxyphenyl)-N-({1-[(2-methoxyphenyl)methyl]-4,5-dimethylimidazol-2-yl}methyl)-N-(3-methylbutyl)carboxamide.
 10. A compound according to claim 1, which is (2-Chloro-3,4- dimethoxyphenyl)-N-({1-[(2-hydroxyphenyl)methyl]4,5-dimethylimidazol-2-yl}methyl)-N-(3-methylbutyl)carboxamide.
 11. A compound according to claim 1, which is Ethyl{2-[(2-{[(2-chloro-3,4-dimethoxyphenyl)-N-(3-methylbutyl)carbonylamino]methyl}-4,5-dimethylimidazol-1-yl)methyl]phenoxy}acetate.
 12. A compound according to claim 1, which is {2-[(2-{[(2-Chloro-3,4-dimethoxyphenyl)-N-(3-methylbutyl)carbonylamino]methyl}-4,5-dimethylimidazol-1-yl)methyl]phenoxy}acetic acid.
 13. A compound according to claim 1, which is (2-Chloro-3,4- dimethoxyphenyl)-N-({1-[(2-cyanophenyl)methyl]4,5-dimethylimidazol-2-yl}methyl)-N-(3-methylbutyl)carboxamide.
 14. A compound according to claim 1, which is 2-{2-{[(2-Chloro-3,4-dimethoxyphenyl)-N-(3-methylbutyl)carbonylamino}methyl]-4,5-dimethylimidazol-1-yl)methyl}benzoic acid.
 15. A compound according to claim 1, which is (2-Chloro-3,4- dimethoxyphenyl)-N-({1-[(2-[cyanomethoxy]-phenyl)methyl]4,5-dimethylimidazol-2-yl}methyl)-N-(3-methylbutyl)carboxamide.
 16. A compound according to claim 1, which is (2-Chloro-3,4-dimethoxyphenyl)-N-{[1-benzyl-4,5-dimethylimidazol-2-yl]methyl}-N-(3-methylbutyl) carboxamide.
 17. A compound according to claim 1, which is (2-Chloro-3,4-dimethoxyphenyl-N-({4,5-dimethyl-1-[(2-methylphenyl)methyl]}imidazol-2-yl}methyl-N-(3-methylbutyl)carboxamide.
 18. A compound according to claim 1, which is (2-Chloro-3,4-dimethoxyphenyl-N-[(4,5-dimethyl-1-{[2-(trifluoromethyl)phenyl]methyl}imidazol-2-yl)methyl]-N-(3-methylbutyl)carboxamide.
 19. A compound according to claim 1, which is N-{[4,5-Dichloro-1-benzylimidazol-2-yl]methyl}(2-chloro-3,4-dimethoxyphenyl)-N-(3-methylbutyl)carboxamide.
 20. A compound according to claim 1, which is N-({4,5-Dichloro-1-[(2-chlorophenyl)methyl]imidazol-2-yl}methyl)(2-chloro-3,4-dimethoxyphenyl)-N-(3-methylbutyl)carboxamide.
 21. A compound according to claim 1, which is N-({4,5-Dichloro-1-[(2-methylphenyl)methyl]imidazol-2-yl}methyl)(2-chloro-3,4-dimethoxyphenyl)-N-(3-methylbutyl)carboxamide.
 22. A compound according to claim 1, which is (2-Chloro-3,4-dimethoxyphenyl)-N-{4,5-diethyl-1-[(5-ethyl-2-methoxyphenyl)methyl]imidazol-2-yl}methyl-N-(3-methylbutyl)carboxamide.
 23. A compound according to claim 1, which is (2-Chloro-3,4- dimethoxyphenyl)-N-({1-[(5-bromo-2-hydroxyphenyl)methyl]4,5-dimethylimidazol-2-yl}methyl-N-(3-methylbutyl)carboxamide.
 24. A compound according to claim 1, which is (2-Chloro-3,4-dimethoxyphenyl)-N-{3,4-dimethyl-1-[(5-chloro-2-hydroxyphenyl)methyl]imidazol-2-yl}methyl-N-(3-methylbutyl)carboxamide.
 25. A compound according to claim 1, which is (2-Chloro-3,4-dimethoxyphenyl)-N-({1-[(2-carboxamidophenyl)methyl]-4,5-dimethylimidazol-2-yl}methyl)-N-(3-methylbutyl)carboxamide.
 26. A compound according to claim 1, which is N-({4,5-Dichloro-1-[(2-carboxamidophenyl)methyl]imidazol-2-yl}methyl)(2-chloro-3,4-dimethoxyphenyl)-N-(3-methylbutyl)carboxamide.
 27. A compound according to claim 1, which is (2-Chloro-3,4-dimethoxyphenyl)-N-({1-[(2-sulfonamidophenyl)methyl]-4,5-dimethylimidazol-2-yl}methyl)-N-(3-methylbutyl)carboxamide.
 28. A compound according to claim 1, which is N-({4,5-Dichloro-1-[(2-sulfonamidophenyl)methyl]imidazol-2-yl}methyl)(2-chloro-3,4-dimethoxyphenyl)-N-(3-methylbutyl)carboxamide.
 29. A pharmaceutical composition comprising a compound according to claim 1, together with at least one pharmaceutically acceptable carrier or excipient.
 30. A method of increasing the permeability of the blood brain barrier, which method comprises administering an effective amount of a compound according to claim 1 to a patient.
 31. A method of increasing the brain concentration of a CNS active compound, which method comprises administering an effective amount of a compound according to any one of claim 1 and the CNS active compound to a patient.
 32. A compound of the formula

or a pharmaceutically acceptable salt, prodrug, or solvate thereof, wherein: R₄ represents straight or branched chain lower alkyl; R₅ represents hydrogen, C₁-C₂alkyl, C₁-C₂alkoxy, —SCH₃, phenyl, benzyl, phenethyl, phenoxy, halogenU or trifluoromethyl; R₆, R₇ and R₇′ are the same or different and represent hydrogen, trifluoromethyl, trifluoromethoxy, nitrile, C₁-C₁₀ alkyl, C₁-C₁₀ alkoxy, C₁-C₆alkylthio, halogen, aminomethyl, di(C₁-C₆)alkylamino, phenyl, phenoxy, mono or diC₁-C₆alkylaminomethyl; and R₁₀ represents methoxy and R₁₁ represents hydrogen, or R₁₀ represents hydrogen and R₁₁ represents methoxy.
 33. A compound according to claim 32 which is selected from compounds (1) through (20): R₄ R₅ R₆ R₇ (1) n-pentyl H —OCH₂CH₃ —OCH₂CH₃ (2) 3-methylbutyl H —OCH₂CH₃ —OCH₂CH₃ (3) n-pentyl H —OCH₂CH₃ —OCH₂CH₃ (4) 3-methylbutyl H —OCH₂CH₃ —OCH₂CH₃ (5) n-pentyl H —CF₃ H (6) 3-methylbutyl H —CF₃ H (7) n-pentyl H —CF₃ H 8) 3-methylbutyl H —CF₃ H (9) n-pentyl H I —CH₃ (10) 3-methylbutyl H I —CH₃ (11) n-pentyl H I —CH₃ (12) 3-methylbutyl H I —CH₃ (13) n-pentyl H H —O(CH₂)₈CH₃ (14) 3-methylbutyl H H —O(CH₂)₈CH₃ (15) n-pentyl H H —O(CH₂)₈CH₃ (16) 3-methylbutyl H H —O(CH₂)₈CH₃ (17) n-pentyl H H —O(CH₂)₉CH₃ (18) 3-methylbutyl H H —O(CH₂)₉CH₃ (19) n-pentyl H H —O(CH₂)₉CH₃ (20) 3-methylbutyl H H —O(CH₂)₉CH₃ R₇′ R₁₀ R₁₁ (1) —OCH₂CH₃ —OCH₃ H (2) —OCH₂CH₃ H —OCH₃ (3) —OCH₂CH₃ H —OCH₃ (4) —OCH₂CH₃ —OCH₃ H (5) —CF₃ —OCH₃ H (6) —CF₃ H —OCH₃ (7) —CF₃ H —OCH₃ (8) —CF₃ —OCH₃ H (9) H —OCH₃ H (10) H H —OCH₃ (11) H H —OCH₃ (12) H —OCH₃ H (13) H —OCH₃ H (14) H H —OCH₃ (15) H H —OCH₃ (16) H —OCH₃ H (17) H —OCH₃ H (18) H H —OCH₃ (19) H H —OCH₃ (20) H —OCH₃ H.


34. A compound according to claim 32 wherein R₆ and R₇ are hydrogen which is selected from compounds (21) through (28): R₄ R₅ R₇′ R₁₀ R₁₁ (21) n-pentyl Cl —SCH₃ —OCH₃ H (22) 3-methylbutyl Cl —SCH₃ H —OCH₃ (23) n-pentyl Cl —SCH₃ H —OCH₃ (24) 3-methylbutyl Cl —SCH₃ —OCH₃ H (25) n-pentyl Br —CH₃ —OCH₃ H (26) 3-methylbutyl Br —CH₃ H —OCH₃ (27) n-pentyl Br —CH₃ H —OCH₃ (28) 3-methylbutyl Br —CH₃ —OCH₃ H.


35. A compound according to claim 32 which is selected from compounds (29) through (52): R₄ R₅ R₆ R₇ (29) n-pentyl Cl H —OCH₃ (30) 3-methylbutyl Cl H —OCH₃ (31) n-pentyl Cl H —OCH₃ (32) 3-methylbutyl Cl H —OCH₃ (33) n-pentyl Br —CH₃ H (34) 3-methylbutyl Br —CH₃ H (35) n-pentyl Br —CH₃ H (36) 3-methylbutyl Br —CH₃ H (37) n-pentyl Cl —CF₃ H (38) 3-methylbutyl Cl —CF₃ H (39) n-pentyl Cl —CF₃ H (40) 3-methylbutyl Cl —CF₃ H (41) n-pentyl Cl H H (42) 3-methylbutyl Cl H H (43) n-pentyl Cl H H (44) 3-methylbutyl Cl H H (45) n-pentyl Br H —OCH₃ (46) 3-methylbutyl Br H —OCH₃ (47) n-pentyl Br H —OCH₃ (48) 3-methylbutyl Br H —OCH₃ (49) n-pentyl —SCH₃ H H (50) 3-methylbutyl —SCH₃ H H (51) n-pentyl —SCH₃ H H (52) 3-methylbutyl —SCH₃ H H R₇′ R₁₀ R₁₁ (29) —OCH₃ —OCH₃ H (30) —OCH₃ H —OCH₃ (31) —OCH₃ H —OCH₃ (32) —OCH₃ —OCH₃ H (33) H —OCH₃ H (34) H H —OCH₃ (35) H H —OCH₃ (36) H —OCH₃ H (37) H —OCH₃ H (38) H H —OCH₃ (39) H H —OCH₃ (40) H —OCH₃ H (41) H —OCH₃ H (42) H H —OCH₃ (43) H H —OCH₃ (44) H —OCH₃ H (45) —OCH₃ —OCH₃ H (46) —OCH₃ H —OCH₃ (47) —OCH₃ H —OCH₃ (48) —OCH₃ —OCH₃ H (49) H —OCH₃ H (50) H H —OCH₃ (51) H H —OCH₃ (52) H —OCH₃ H.


36. A compound according to claim 32, wherein R₇′ is hydrogen which is selected from compounds (53) through (80): R₄ R₅ R₆ R₇ R₁₀ R₁₁ (53) n-pentyl H H H —OCH₃ H (54) 3- H H H H —OCH₃ methylbutyl (55) n-pentyl H H H H —OCH₃ (56) 3- H H H —OCH₃ H methylbutyl (57) n-pentyl H —CH₃ H —OCH₃ H (58) 3- H —CH₃ H H —OCH₃ methylbutyl (59) n-pentyl H —CH₃ H H —OCH₃ (60) 3- H —CH₃ H —OCH₃ H methylbutyl (61) n-pentyl H H —CH₃ —OCH₃ H (62) 3- H H —CH₃ H —OCH₃ methylbutyl (63) n-pentyl H H —CH₃ H —OCH₃ (64) 3- H H —CH₃ —OCH₃ H methylbutyl (65) n-pentyl —CH₃ H H —OCH₃ H (66) 3- —CH₃ H H H —OCH₃ methylbutyl (67) n-pentyl —CH₃ H H H —OCH₃ (68) 3- —CH₃ H H —OCH₃ H methylbutyl (69) n-pentyl H F H —OCH₃ H (70) 3- H F H H —OCH₃ methylbutyl (71) n-pentyl H F H H —OCH₃ (72) 3- H F H —OCH₃ H methylbutyl (73) n-pentyl H H F —OCH₃ H (74) 3- H H F H —OCH₃ methylbutyl (75) n-pentyl H H F H —OCH₃ (76) 3- H H F —OCH₃ H methylbutyl (77) n-pentyl H H H —OCH₃ H (78) 3- H H H H —OCH₃ methylbutyl (79) n-pentyl H H H H —OCH₃ (80) 3- H H H —OCH₃ H methylbutyl


37. A compound according to claim 1 which is selected from compounds (81) through (104): R₄ R₅ R₆ R₇ (81) n-pentyl H H —CH₂CH₃ (82) 3-methylbutyl H H —CH₂CH₃ (83) n-pentyl H H —CH₂CH₃ (84) 3-methylbutyl H H —CH₂CH₃ (85) n-pentyl H —CH₃ —CH₃ (86) 3-methylbutyl H —CH₃ —CH₃ (87) n-pentyl H —CH₃ —CH₃ (88) 3-methylbutyl H —CH₃ —CH₃ (89) n-pentyl H —CH₃ H (90) 3-methylbutyl H —CH₃ H (91) n-pentyl H —CH₃ H (92) 3-methylbutyl H —CH₃ H (93) n-pentyl H —CH₃ H (94) 3-methylbutyl H —CH₃ H (95) n-pentyl H —CH₃ H (96) 3-methylbutyl H —CH₃ H (97) n-pentyl H H H (98) 3-methylbutyl H H H (99) n-pentyl H H H (100) 3-methylbutyl H H H (101) n-pentyl —CH₃ H —CH₃ (102) 3-methylbutyl —CH₃ H —CH₃ (103) n-pentyl —CH₃ H —CH₃ (104) 3-methylbutyl —CH₃ H —CH₃ R₇′ R₁₀ R₁₁ (81) H —OCH₃ H (82) H H —OCH₃ (83) H H —OCH₃ (84) H —OCH₃ H (85) H —OCH₃ H (86) H H —OCH₃ (87) H H —OCH₃ (88) H —OCH₃ H (89) —CH₃ —OCH₃ H (90) —CH₃ H —OCH₃ (91) —CH₃ H —OCH₃ (92) —CH₃ —OCH₃ H (93) H —OCH₃ H (94) H H —OCH₃ (95) H H —OCH₃ (96) H —OCH₃ H (97) —CH₃ —OCH₃ H (98) —CH₃ H —OCH₃ (99) —CH₃ H —OCH₃ (100) —CH₃ —OCH₃ H (101) H —OCH₃ H (102) H H —OCH₃ (103) H H —OCH₃ (104) H —OCH₃ H.


38. A compound according to claim 32 which is selected from compounds (105) through (132): R₄ R₅ R₆ R₇ (105) n-pentyl H —OCH₃ H (106) 3-methylbutyl H —OCH₃ H (107) n-pentyl H —OCH₃ H (108) 3-methylbutyl H —OCH₃ H (109) n-pentyl H H —OCH₃ (110) 3-methylbutyl H H —OCH₃ (111) n-pentyl H H —OCH₃ (112) 3-methylbutyl H H —OCH₃ (113) n-pentyl —OCH₃ H H (114) 3-methylbutyl —OCH₃ H H (115) n-pentyl —OCH₃ H H (116) 3-methylbutyl —OCH₃ H H (117) n-pentyl H F —CH₃ (118) 3-methylbutyl H F —CH₃ (119) n-pentyl H F —CH₃ (120) 3-methylbutyl H F —CH₃ (121) n-pentyl —CH₃ F H (122) 3-methylbutyl —CH₃ F H (123) n-pentyl —CH₃ F H (124) 3-methylbutyl —CH₃ F H (125) n-pentyl —CH₃ H H (126) 3-methylbutyl —CH₃ H H (127) n-pentyl —CH₃ H H (128) 3-methylbutyl —CH₃ H H (129) n-pentyl F —CH₃ H (130) 3-methylbutyl F —CH₃ H (131) n-pentyl F —CH₃ H (132) 3-methylbutyl F —CH₃ H R₇′ R₁₀ R₁₁ (105) H —OCH₃ H (106) H H —OCH₃ (107) H H —OCH₃ (108) H —OCH₃ H (109) H —OCH₃ H (110) H H —OCH₃ (111) H H —OCH₃ (112) H —OCH₃ H (113) H —OCH₃ H (114) H H —OCH₃ (115) H H —OCH₃ (116) H —OCH₃ H (117) H —OCH₃ H (118) H H —OCH₃ (119) H H —OCH₃ (120) H —OCH₃ H (121) H —OCH₃ H (122) H H —OCH₃ (123) H H —OCH₃ (124) H —OCH₃ H (125) F —OCH₃ H (126) F H —OCH₃ (127) F H —OCH₃ (128) F —OCH₃ H (129) H —OCH₃ H (130) H H —OCH₃ (131) H H —OCH₃ (132) H —OCH₃ H.


39. A compound according to claim 32 which is selected from compounds (133) through (156): R₄ R₅ R₆ R₇ R₇′ R₁₀ R₁₁ (133) n-pentyl H Cl H H —OCH₃ H (134) 3-methylbutyl H Cl H H H —OCH₃ (135) n-pentyl H Cl H H H —OCH₃ (136) 3-methylbutyl H Cl H H —OCH₃ H (137) n-pentyl H H Cl H —OCH₃ H (138) 3-methylbutyl H H Cl H H —OCH₃ (139) n-pentyl H H Cl H H —OCH₃ (140) 3-methylbutyl H H Cl H —OCH₃ H (141) n-pentyl Cl H H H —OCH₃ H (142) 3-methylbutyl Cl H H H H —OCH₃ (143) n-pentyl Cl H H H H —OCH₃ (144) 3-methylbutyl Cl H H H —OCH₃ H (145) n-pentyl H F F H —OCH₃ H (146) 3-methylbutyl H F F H H —OCH₃ (147) n-pentyl H F F H H —OCH₃ (148) 3-methylbutyl H F F H —OCH₃ H (149) n-pentyl F F H H —OCH₃ H (150) 3-methylbutyl F F H H H —OCH₃ (151) n-pentyl F F H H H —OCH₃ (152) 3-methylbutyl F F H H —OCH₃ H (153) n-pentyl F H H F —OCH₃ H (154) 3-methylbutyl F H H F H —OCH₃ (155) n-pentyl F H H F H —OCH₃ (156) 3-methylbutyl F H H F —OCH₃ H.


40. A compound according to claim 32 which is selected from compounds (157) through (180): R₄ R₅ R₆ (157) n-pentyl F H (158) 3-methylbutyl F H (159) n-pentyl F H (160) 3-methylbutyl F H (161) n-pentyl H H (162) 3-methylbutyl H H (163) n-pentyl H H (164) 3-methylbutyl H H (165) n-pentyl H H (166) 3-methylbutyl H H (167) n-pentyl H H (168) 3-methylbutyl H H (169) n-pentyl H —OCH₂CH₃ (170) 3-methylbutyl H —OCH₂CH₃ (171) n-pentyl H —OCH₂CH₃ (172) 3-methylbutyl H —OCH₂CH₃ (173) n-pentyl H H (174) 3-methylbutyl H H (175) n-pentyl H H (176) 3-methylbutyl H H (177) n-pentyl —OCH₂CH₃ H (178) 3-methylbutyl —OCH₂CH₃ H (179) n-pentyl —OCH₂CH₃ H (180) 3-methylbutyl —OCH₂CH₃ H R₇ R₇′ R₁₀ R₁₁ (157) F H —OCH₃ H (158) F H H —OCH₃ (159) F H H —OCH₃ (160) F H —OCH₃ H (161) —CH₂CH₃ H —OCH₃ H (162) —CH₂CH₃ H H —OCH₃ (163) —CH₂CH₃ H H —OCH₃ (164) —CH₂CH₃ H —OCH₃ H (165) —CH(CH₃)₂ H —OCH₃ H (166) —CH(CH₃)₂ H H —OCH₃ (167) —CH(CH₃)₂ H H —OCH₃ (168) —CH(CH₃)₂ H —OCH₃ H (169) H H —OCH₃ H (170) H H H —OCH₃ (171) H H H —OCH₃ (172) H H —OCH₃ H (173) —OCH₂CH₃ H —OCH₃ H (174) —OCH₂CH₃ H H —OCH₃ (175) —OCH₂CH₃ H H —OCH₃ (176) —OCH₂CH₃ H —OCH₃ H (177) H H —OCH₃ H (178) H H H —OCH₃ (179) H H H —OCH₃ (180) H H —OCH₃ H.


41. A compound according to claim 32 which is selected from compounds (185) through (240): R₄ R₅ R₆ R₇ (185) n-pentyl H H —SCH₃ (186) 3-methylbutyl H H —SCH₃ (187) n-pentyl H H —SCH₃ (188) 3-methylbutyl H H —SCH₃ (189) n-pentyl H F —OCH₃ (190) 3-methylbutyl H F —OCH₃ (191) n-pentyl H F —OCH₃ (192) 3-methylbutyl H F —OCH₃ (193) n-pentyl H —CH₃ Cl (194) 3-methylbutyl H —CH₃ Cl (195) n-pentyl H —CH₃ Cl (196) 3-methylbutyl H —CH₃ Cl (197) n-pentyl H Cl F (198) 3-methylbutyl H Cl F (199) n-pentyl H Cl F (200) 3-methylbutyl H Cl F (201) n-pentyl H F F (202) 3-methylbutyl H F F (203) n-pentyl H F F (204) 3-methylbutyl H F F (205) n-pentyl H H —(CH₂)₃CH₃ (206) 3-methylbutyl H H —(CH₂)₃CH₃ (207) n-pentyl H H —(CH₂)₃CH₃ (208) 3-methylbutyl H H —(CH₂)₃CH₃ (209) n-pentyl H H —C(CH₃)₃ (210) 3-methylbutyl H H —C(CH₃)₃ (211) n-pentyl H H —C(CH₃)₃ (212) 3-methylbutyl H H —C(CH₃)₃ (213) n-pentyl H H —O(CH₂)₂CH₃ (214) 3-methylbutyl H H —O(CH₂)₂CH₃ (215) n-pentyl H H —O(CH₂)₂CH₃ (216) 3-methylbutyl H H —O(CH₂)₂CH₃ (217) n-pentyl H H —OCH(CH₃)₂ (218) 3-methylbutyl H H —OCH(CH₃)₂ (219) n-pentyl H H —OCH(CH₃)₂ (220) 3-methylbutyl H H —OCH(CH₃)₂ (221) n-pentyl H H —SCH₂CH₃ (222) 3-methylbutyl H H —SCH₂CH₃ (223) n-pentyl H H —SCH₂CH₃ (224) 3-methylbutyl H H —SCH₂CH₃ (225) n-pentyl H —OCH₃ —OCH₃ (226) 3-methylbutyl H —OCH₃ —OCH₃ (227) n-pentyl H —OCH₃ —OCH₃ (228) 3-methylbutyl H —OCH₃ —OCH₃ (229) n-pentyl H —OCH₃ H (230) 3-methylbutyl H —OCH₃ H (231) n-pentyl H —OCH₃ H (232) 3-methylbutyl H —OCH₃ H (233) n-pentyl —OCH₃ —OCH₃ H (234) 3-methylbutyl —OCH₃ —OCH₃ H (235) n-pentyl —OCH₃ —OCH₃ H (236) 3-methylbutyl —OCH₃ —OCH₃ H (237) n-pentyl —OCH₃ H H (238) 3-methylbutyl —OCH₃ H H (239) n-pentyl —OCH₃ H H (240) 3-methylbutyl —OCH₃ H H R₇ ′ R₁₀ R₁₁ (181) H —OCH₃ H (182) H H —OCH₃ (183) H H —OCH₃ (184) H —OCH₃ H (185) H —OCH₃ H (186) H H —OCH₃ (187) H H —OCH₃ (188) H —OCH₃ H (189) H —OCH₃ H (190) H H —OCH₃ (191) H H —OCH₃ (192) H —OCH₃ H (193) H —OCH₃ H (194) H H —OCH₃ (195) H H —OCH₃ (196) H —OCH₃ H (197) H —OCH₃ H (198) H H —OCH₃ (199) H H —OCH₃ (200) H —OCH₃ H (201) F —OCH₃ H (202) F H —OCH₃ (203) F H —OCH₃ (204) F —OCH₃ H (205) H —OCH₃ H (206) H H —OCH₃ (207) H H —OCH₃ (208) H —OCH₃ H (209) H —OCH₃ H (210) H H —OCH₃ (211) H H —OCH₃ (212) H —OCH₃ H (213) H —OCH₃ H (214) H H —OCH₃ (215) H H —OCH₃ (216) H —OCH₃ H (217) H —OCH₃ H (218) H H —OCH₃ (219) H H —OCH₃ (220) H —OCH₃ H (221) H —OCH₃ H (222) H H —OCH₃ (223) H H —OCH₃ (224) H —OCH₃ H (225) H —OCH₃ H (226) H H —OCH₃ (227) H H —OCH₃ (228) H —OCH₃ H (229) —OCH₃ —OCH₃ H (230) —OCH₃ H —OCH₃ (231) —OCH₃ H —OCH₃ (232) —OCH₃ —OCH₃ H (233) H —OCH₃ H (234) H H —OCH₃ (235) H H —OCH₃ (236) H —OCH₃ H (237) —OCH₃ —OCH₃ H (238) —OCH₃ H —OCH₃ (239) —OCH₃ H —OCH₃ (240) —OCH₃ —OCH₃ H.


42. A compound according to claim 32 which is selected from compound (241) through (300): R₄ R₅ R₆ (241) n-pentyl —OCH₃ H (242) 3-methylbutyl —OCH₃ H (243) n-pentyl —OCH₃ H (244) 3-methylbutyl —OCH₃ H (245) n-pentyl H Cl (246) 3-methylbutyl H Cl (247) n-pentyl H Cl (248) 3-methylbutyl H Cl (249) n-pentyl —OCH₃ H (250) 3-methylbutyl —OCH₃ H (251) n-pentyl —OCH₃ H (252) 3-methylbutyl —OCH₃ H (253) n-pentyl —OCH₃ H (254) 3-methylbutyl —OCH₃ H (255) n-pentyl —OCH₃ H (256) 3-methylbutyl —OCH₃ H (257) n-pentyl H CF₃ (258) 3-methylbutyl H CF₃ (259) n-pentyl H CF₃ (260) 3-methylbutyl H CF₃ (261) n-pentyl H H (262) 3-methylbutyl H H (263) n-pentyl H H (264) 3-methylbutyl H H (265) n-pentyl CF₃ H (266) 3-methylbutyl CF₃ H (267) n-pentyl CF₃ H (268) 3-methylbutyl CF₃ H (269) n-pentyl H Cl (270) 3-methylbutyl H Cl (271) n-pentyl H Cl (272) 3-methylbutyl H Cl (273) n-pentyl H Cl (274) 3-methylbutyl H Cl (275) n-pentyl H Cl (276) 3-methylbutyl H Cl (277) n-pentyl Cl Cl (278) 3-methylbutyl Cl Cl (279) n-pentyl Cl Cl (280) 3-methylbutyl Cl Cl (281) n-pentyl Cl H (282) 3-methylbutyl Cl H (283) n-pentyl Cl H (284) 3-methylbutyl Cl H (285) n-pentyl Cl H (286) 3-methylbutyl Cl H (287) n-pentyl Cl H (288) 3-methylbutyl Cl H (289) n-pentyl H H (290) 3-methylbutyl H H (291) n-pentyl H H (292) 3-methylbutyl H H (293) n-pentyl H H (294) 3-methylbutyl H H (295) n-pentyl H H (296) 3-methylbutyl H H (297) n-pentyl H H (298) 3-methylbutyl H H (299) n-pentyl H H (300) 3-methylbutyl H H R₇ R₇′ R₁₀ R₁₁ (241) —OCH₃ H —OCH₃ H (242) —OCH₃ H H —OCH₃ (243) —OCH₃ H H —OCH₃ (244) —OCH₃ H —OCH₃ H (245) —OCH₃ H —OCH₃ H (246) —OCH₃ H H —OCH₃ (247) —OCH₃ H H —OCH₃ (248) —OCH₃ H —OCH₃ H (249) H Cl —OCH₃ H (250) H Cl H —OCH₃ (251) H Cl H —OCH₃ (252) H Cl —OCH₃ H (253) Cl H —OCH₃ H (254) Cl H H —OCH₃ (255) Cl H H —OCH₃ (256) Cl H —OCH₃ H (257) H H —OCH₃ H (258) H H H —OCH₃ (259) H H H —OCH₃ (260) H H —OCH₃ H (261) CF₃ H —OCH₃ H (262) CF₃ H H —OCH₃ (263) CF₃ H H —OCH₃ (264) CF₃ H —OCH₃ H (265) H H —OCH₃ H (266) H H H —OCH₃ (267) H H H —OCH₃ (268) H H —OCH₃ H (269) Cl H —OCH₃ H (270) Cl H H —OCH₃ (271) Cl H H —OCH₃ (272) Cl H —OCH₃ H (273) H Cl —OCH₃ H (274) H Cl H —OCH₃ (275) H Cl H —OCH₃ (276) H Cl —OCH₃ H (277) H H —OCH₃ H (278) H H H —OCH₃ (279) H H H —OCH₃ (280) H H —OCH₃ H (281) H Cl —OCH₃ H (282) H Cl H —OCH₃ (283) H Cl H —OCH₃ (284) H Cl —OCH₃ H (285) Cl H —OCH₃ H (286) Cl H H —OCH₃ (287) Cl H H —OCH₃ (288) Cl H —OCH₃ H (289) —(CH₂)₄CH₃ H —OCH₃ H (290) —(CH₂)₄CH₃ H H —OCH₃ (291) —(CH₂)₄CH₃ H H —OCH₃ (292) —(CH₂)₄CH₃ H —OCH₃ H (293) —O(CH₂)₃CH₃ H —OCH₃ H (294) —O(CH₂)₃CH₃ H H —OCH₃ (295) —O(CH₂)₃CH₃ H H —OCH₃ (296) —O(CH₂)₃CH₃ H —OCH₃ H (297) phenyl H —OCH₃ H (298) phenyl H H —OCH₃ (299) phenyl H H —OCH₃ (300) phenyl H —OCH₃ H.


43. A compound according to claim 32 which is selected from compounds (301) through (350): R₄ R₅ R₆ (301) n-pentyl phenyl H (302) 3-methylbutyl phenyl H (303) n-pentyl phenyl H (304) 3-methylbutyl phenyl H (305) n-pentyl H Br (306) 3-methylbutyl H Br (307) n-pentyl H Br (308) 3-methylbutyl H Br (309) n-pentyl H H (310) 3-methylbutyl H H (311) n-pentyl H H (312) 3-methylbutyl H H (313) n-pentyl Br H (314) 3-methylbutyl Br H (315) n-pentyl Br H (316) 3-methylbutyl Br H (317) n-pentyl H H (318) 3-methylbutyl H H (319) n-pentyl H H (320) 3-methylbutyl H H (321) n-pentyl H H (322) 3-methylbutyl H H (323) n-pentyl H H (324) 3-methylbutyl H H (325) n-pentyl H H (326) 3-methylbutyl H H (327) n-pentyl H H (328) 3-methylbutyl H H (329) n-pentyl F CF₃ (330) 3-methylbutyl F CF₃ (331) n-pentyl F CF₃ (332) 3-methylbutyl F CF₃ (333) n-pentyl H —OCH₂CH₃ (334) 3-methylbutyl H —OCH₂CH₃ (335) n-pentyl H —OCH₂CH₃ (336) 3-methylbutyl H —OCH₂CH₃ (337) n-pentyl H —OCH₃ (338) 3-methylbutyl H —OCH₃ (339) n-pentyl H —OCH₃ (340) 3-methylbutyl H —OCH₃ (341) n-pentyl —OCH₃ —OCH₃ (342) 3-methylbutyl —OCH₃ —OCH₃ (343) n-pentyl —OCH₃ —OCH₃ (344) 3-methylbutyl —OCH₃ —OCH₃ (345) n-pentyl benzyl H (346) 3-methylbutyl benzyl H (347) n-pentyl benzyl H (348) 3-methylbutyl benzyl H R₇ R₇′ R₁₀ R₁₁ (301) H H —OCH₃ H (302) H H H —OCH₃ (303) H H H —OCH₃ (304) H H —OCH₃ H (305) H H —OCH₃ H (306) H H H —OCH₃ (307) H H H —OCH₃ (308) H H —OCH₃ H (309) Br H —OCH₃ H (310) Br H H —OCH₃ (311) Br H H —OCH₃ (312) Br H —OCH₃ H (313) H H —OCH₃ H (314) H H H —OCH₃ (315) H H H —OCH₃ (316) H H —OCH₃ H (317) —(CH₂)₅CH₃ H —OCH₃ H (318) —(CH₂)₅CH₃ H H —OCH₃ (319) —(CH₂)₅CH₃ H H —OCH₃ (320) —(CH₂)₅CH₃ H —OCH₃ H (321) —OCF₃ H —OCH₃ H (322) —OCF₃ H H —OCH₃ (323) —OCF₃ H H —OCH₃ (324) —OCF₃ H —OCH₃ H (325) —O(CH₂)₄CH₃ H —OCH₃ H (326) —O(CH₂)₄CH₃ H H —OCH₃ (327) —O(CH₂)₄CH₃ H H —OCH₃ (328) —O(CH₂)₄CH₃ H —OCH₃ H (329) H H —OCH₃ H (330) H H H —OCH₃ (331) H H H —OCH₃ (332) H H —OCH₃ H (333) —OCH₂CH₃ H —OCH₃ H (334) —OCH₂CH₃ H H —OCH₃ (335) —OCH₂CH₃ H H —OCH₃ (336) —OCH₂CH₃ H —OCH₃ H (337) —OCH₃ —OCH₃ —OCH₃ H (338) —OCH₃ —OCH₃ H —OCH₃ (339) —OCH₃ —OCH₃ H —OCH₃ (340) —OCH₃ —OCH₃ —OCH₃ H (341) —OCH₃ H —OCH₃ H (342) —OCH₃ H H —OCH₃ (343) —OCH₃ H H —OCH₃ (344) —OCH₃ H —OCH₃ H (345) H H —OCH₃ H (346) H H H —OCH₃ (347) H H H —OCH₃ (348) H H —OCH₃ H.


44. A compound according to claim 32 which is selected from compounds (349) through (404): R₄ R₅ R₆ (349) n-pentyl H phenoxy (350) 3-methylbutyl H phenoxy (351) n-pentyl H phenoxy (352) 3-methylbutyl H phenoxy (353) n-pentyl H H (354) 3-methylbutyl H H (355) n-pentyl H H (356) 3-methylbutyl H H (357) n-pentyl phenoxy H (358) 3-methylbutyl phenoxy H (359) n-pentyl phenoxy H (360) 3-methylbutyl phenoxy H (361) n-pentyl H Br (362) 3-methylbutyl H Br (363) n-pentyl H Br (364) 3-methylbutyl H Br (365) n-pentyl H Br (366) 3-methylbutyl H Br (367) n-pentyl H Br (368) 3-methylbutyl H Br (369) n-pentyl H H (370) 3-methylbutyl H H (371) n-pentyl H H (372) 3-methylbutyl H H (373) n-pentyl H H (374) 3-methylbutyl H H (375) n-pentyl H H (376) 3-methylbutyl H H (377) n-pentyl phenethyl H (378) 3-methylbutyl phenethyl H (379) n-pentyl phenethyl H (380) 3-methylbutyl phenethyl H (381) n-pentyl H H (382) 3-methylbutyl H H (383) n-pentyl H H (384) 3-methylbutyl H H (385) n-pentyl H H (386) 3-methylbutyl H H (387) n-pentyl H H (388) 3-methylbutyl H H (389) n-pentyl H I (390) 3-methylbutyl H I (391) n-pentyl H I (392) 3-methylbutyl H I (393) n-pentyl H H (394) 3-methylbutyl H H (395) n-pentyl H H (396) 3-methylbutyl H H (397) n-pentyl I H (398) 3-methylbutyl I H (399) n-pentyl I H (400) 3-methylbutyl I H (401) n-pentyl H H (402) 3-methylbutyl H H (403) n-pentyl H H (404) 3-methylbutyl H H R₇ R₇′ R₁₀ R₁₁ (349) H H —OCH₃ H (350) H H H —OCH₃ (351) H H H —OCH₃ (352) H H —OCH₃ H (353) phenoxy H —OCH₃ H (354) phenoxy H H —OCH₃ (355) phenoxy H H —OCH₃ (356) phenoxy H —OCH₃ H (357) H H —OCH₃ H (358) H H H —OCH₃ (359) H H H —OCH₃ (360) H H —OCH₃ H (361) —CH₃ H —OCH₃ H (362) —CH₃ H H —OCH₃ (363) —CH₃ H H —OCH₃ (364) —CH₃ H —OCH₃ H (365) F H —OCH₃ H (366) F H H —OCH₃ (367) F H H —OCH₃ (368) F H —OCH₃ H (369) —(CH₂)₆CH₃ H —OCH₃ H (370) —(CH₂)₆CH₃ H H —OCH₃ (371) —(CH₂)₆CH₃ H H —OCH₃ (372) —(CH₂)₆CH₃ H —OCH₃ H (373) —O(CH₂)₅CH₃ H —OCH₃ H (374) —O(CH₂)₅CH₃ H H —OCH₃ (375) —O(CH₂)₅CH₃ H H —OCH₃ (376) —O(CH₂)₅CH₃ H —OCH₃ H (377) H H —OCH₃ H (378) H H H —OCH₃ (379) H H H —OCH₃ (380) H H —OCH₃ H (381) —(CH₂)₇CH₃ H —OCH₃ H (382) —(CH₂)₇CH₃ H H —OCH₃ (383) —(CH₂)₇CH₃ H H —OCH₃ (384) —(CH₂)₇CH₃ H —OCH₃ H (385) —O(CH₂)₆CH₃ H —OCH₃ H (386) —O(CH₂)₆CH₃ H H —OCH₃ (387) —O(CH₂)₆CH₃ H H —OCH₃ (388) —O(CH₂)₆CH₃ H —OCH₃ H (389) H H —OCH₃ H (390) H H H —OCH₃ (391) H H H —OCH₃ (392) H H —OCH₃ H (393) I H —OCH₃ H (394) I H H —OCH₃ (395) I H H —OCH₃ (396) I H —OCH₃ H (397) H H —OCH₃ H (398) H H H —OCH₃ (399) H H H —OCH₃ (400) H H —OCH₃ H (401) —O(CH₂)₇CH₃ H —OCH₃ H (402) —O(CH₂)₇CH₃ H H —OCH₃ (403) —O(CH₂)₇CH₃ H H —OCH₃ (404) —O(CH₂)₇CH₃ H —OCH₃ H


45. A method of increasing the permeability of the blood brain barrier, which method comprises administering an effective amount of a compound according to claim 1 to a patient.
 46. A method of increasing the brain concentration of a CNS active compound, which method comprises administering an effective amount of a compound according to any one of claim 1 and the CNS active compound to a patient. 